Surgical Management of Cushing’s Disease and Acromegaly

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- Hello ladies and gentlemen, and thank you for joining us for another session of The Virtual Operating Room from the Neurosurgical Atlas. Our guest today is Dr. John Jane, from University of Virginia. John is a dear friend. He's the professor of neurosurgery at UVA and also the Director of Pediatric Neurosurgery, as well as the program director there. John has a tremendous experience for managing parasellar lesions, especially through the endonasal route. And I'm so pleased and honored to have you with us, John. So we're really excited to learn from you about surgical management of Cushing's disease and acromegaly. Cushing's disease, obviously one of the most difficult lesions, to treat by endonasal route. So with that in mind, thank you again John and please go ahead.

- Aaron thank you. So as this gets started, of course, I want to acknowledge what an honor it is to be, a part of the Neurosurgical Atlas. You should feel proud of what you have done, and it's a tremendous service to the neurosurgical community. So a pleasure to be a part of it.

- Thank you.

- So what I thought I'd talk about is something that I'm excited to talk about, which is Cushing's disease and acromegaly, and in particular, the surgical considerations or surgical nuances surrounding the care of these patients. I don't have any, I don't have any disclosures. I would want to acknowledge the team that I work with. And I think in particular, in pituitary surgery it is tremendously helpful to have assembled a multidisciplinary team of truly excellent people. And among those people are included neuroradiologists, neuro-ophthalmologist, the neuropathologist, of course, Gamma Knife radiosurgery plays a role in the care of patients. The tremendous endocrinologists that I work with, and also importantly, in the operating room, the otolaryngologists, the Rhinologists with whom I get to work, a couple of times a week, every week of my life. I'd also acknowledge my mentors from the past. Many of you, of course know it was who, taught me pituitary surgery, using the microscope as a resident and encouraged me to use the endoscope, when I came on faculty. He has always had a vision to the future and was a tremendous influence on me. In addition Ed Oldfield, who I was colleagues with, from 2007 until 2017, and who influenced me tremendously on my thoughts about the care of patients with Cushing's and also the use of the pseudocapsule of which I will talk a little bit today. Michael Thorner seated here is the endocrinologist with whom Ed Laws started the multidisciplinary clinic at UVA, which I also think is a key feature of proper care of these patients seeing them in the same clinic setting with both the surgeon and the endocrinologist in one setting, in the same room. So for those of you who are interested in Cushing's disease, I would strongly encourage you to read these two journal articles that Ed Oldfield wrote, near the end of his career, both with Russ Lonser and Lynette Neiman at the NIH and his lessons learned, his nuances from over 1500 cases of Cushing's. These are tremendous resources. And I use a number of the figures in this talk. I would say that key in Cushing's is proper diagnosis, that before bringing a patient to the operating room who has Cushing's, one must be certain that the correct diagnosis has been made. And this is amongst all of the pituitary adenomas, this is the most complicated diagnosis to make. And although many of us rely on our endocrinologist to help with the diagnosis. It is crucial for neurosurgeons to understand the the workup, understand the meaning of the tests, so that they don't just find themselves in the operating room, on a patient who really shouldn't be there. So that proper diagnosis, when to go on and do inferior petrosal sinus sampling is a key feature in the care of these patients. What was really emphasized to me by Ed Oldfield, was the use of the pseudocapsule in the resection of these tumors. Now he did these cases through the microscope. I was and continue to try to mimic what he did with the endoscope and hopefully in time I will get close to doing it almost as well as he did, although I think he really was the ideal in terms of resection of these small tumors. And so the key with these tumors is an acknowledgement that there is a pseudocapsule and again, it is called a pseudocapsule because the capsule that is surrounding these tumors is not a tumor capsule, it is compressed normal gland. And so that if you can go around the tumor, maintaining that pseudocapsule, you are assured that you have done a complete resection of the tumor. It is almost like removing a tumor with a margin. And what Ed Oldfield found was, that once a tumor is three millimeters in size, that they will fairly reliably have, a distinct pseudocapsule. Tumors smaller than that it's highly variable. And so between the two and three millimeter range, less reliable, less than two millimeters, most often there is not a distinct pseudocapsule. But let's look at a resection done by Ed Oldfield. And what you'll see is that he makes an initial incision, that initial incision what you have to understand is, that initial incision is being made through the pituitary capsule one and two normal gland. That is to get on top of the pseudocapsule, so you cannot immediately start operating, without first making an incision in the pituitary capsule, and then the gland, to be on top of the pseudo capsule. If as you're dissecting around a tumor, you start feeling a resistance or a tug, that means that you're either not in the correct plane, or you haven't fully cut through the pituitary capsule and the pituitary gland to be on top of the pseudocapsule. Now, that's great. Thank you next slide. So that is really the ideal. That is what we look for, and if you do that and you take out the tumor, what you'll notice is that there will be a surrounding the tumor a thin layer of compressed normal gland and that compressed normal gland will be running here, like an onion skin, and you see it in higher magnification. And yes at times there are tumor cells that you can see within that pseudocapsule. But the key is removing the tumor with this pseudocapsule and the tumor is within it. And so you're essentially removing a tumor with a margin. Let me, let me. So here is here, here is, I don't see how to take off those markings, can't remember that. So here is a case in which I did not remove the tumor with the pseudocapsule. So it's a perfect tumor, nice small tumor in the front, but this, I believe the pseudocapsule is important enough, that after failing to remove it, and removing the tumor piecemeal, one should go back and find that pseudocapsule. And this is simply me going back after having failed to take it out with the pseudocapsule, finding the pseudocapsule and removing it. Now in this circumstance, you're assured that you haven't left tumor behind. If you had left that pseudocapsule, there's a chance that tumor cells would have been left on the tumor. Next slide please. And so if you do that, if you remove tumors with the pseudocapsule and you compare the cases in which the tumors were removed with the pseudocapsule versus without the pseudocapsule, what you'll notice is a tremendous difference between the two in terms of how rapidly the cortisol levels will drop after surgery, obviously much more rapid with the pseudocapsular resection versus a piecemeal resection. And what we theorized in this paper years ago, was that likely that this reflected the fact that you have done a complete resection versus potentially leaving tumor cells behind. And years later and more recently in 2018, out of the NIH, one of our current residents, Natasha Ironside has published a paper confirming, the fact that patients who experienced a more rapid and more profound drop in their cortisol levels after surgery, are more likely to have a sustained remission and not experience a recurrence. And so, this I believe is a testimony to the reasons that we attempt to remove tumors using the pseudocapsule. So there are a number of special circumstances in the treatment of patients who have Cushing's, a large percentage of our patients, who we treat, who have Cushing's have MRIs that are negative that don't have a definitive tumor. What do you do when you operate on a patient and you have an immediate surgical failure, what's the right step? How do you manage that? Is there a role for an acute re-operation, and what do you do in the setting of recurrent Cushing's disease? So I think step one is in MRI Negative Cushing's is, is it actually negative? And what you have to assess in that situation is what imaging studies were actually done. And, I was involved in a paper, that really was the brainchild of Ed Oldfield, which was to look at the value of the VIBE sequences, or SPGR sequences, over and above, the standard post-contrast T1-weighted imaging. And what we essentially found was, that the SPGR or VIBE sequences are much more sensitive in finding surgical targets than either the dynamic scans or the conventional T1-weighted imaging. And so I would strongly encourage people to choose and ask your radiologist to make sure that the VIBE sequences are part of your protocol and not just part of your protocol, but the first set of post-contrast images that are performed, because the first set of images after contrast is given is your ideal image. And if VIBE is superior to dynamic and is superior to the conventional T1-weighted post-contrast images, you should be asking for VIBE to be part of it, not just part of it, but as your first set of sequences. If a tumor is not seen on the VIBE and conventional, it is then that I asked for a completely separate, dynamic MRI to be performed. So I don't do all of these together in one MRI. If you have a small tumor, it is likely that I'm going to be ordering two separate MRIs, one with the SPGR, and if that shows the tumor, great I stop there, but if it doesn't, then I order a separate Dynamic MRI. So in the setting where it's MRI negative, I have already done IPSS and at times it will lateralize, if it lateralizes, I will look at that side first, and these are simply images showing the incisions that are made within the gland. And this is showing the first image in the midline, but really that isn't the first slice that's made. If it is lateralized, I will make the first slice to the side and search through the gland, looking for tumor, then make another incision, looking for the tumor, and then go across and continue from the lateralization side across to the side that did not lateralize. If I at that point, find a tumor great, I stop at any of these given points and vigilant about sending all the tissue to pathology. If I don't find a tumor, then I will remove a wing, sending it separately, the other wing and then the floor, all of this will be removed, leaving a portion of gland to still be connected to the pituitary stalk. So I will not do a total hypophysectomy. And in this setting, the results are about 70% for remission at one year. So in the setting of a surgery is done, the surgery does not produce an immediate remission, then there are certain steps I have to take because when patients are in the hospital, after I do surgery I don't give them any steroids. And we check cortisol levels every six hours. So we do it at midnight, 6:00 AM, noon, 6:00 PM. And we just continue to check cortisol levels until a patient's cortisol has gone to one or less. And once it reaches a level of one or less, I stop checking cortisols and replace with hydrocortisone. But if my initial surgery does not produce that profound drop in cortisol levels, then I will re-image look to see, is there any obvious tumor that I left behind? If, because I send the specimen separately, if the pathologist says, "John there was tumor on the left side," then I will say, well then I didn't completely remove that tumor, I need to go back in and look at that side. If however, the histology and the imaging was negative, and I had already done a subtotal hypophysectomy, if I had already done this operation, then there is no more for me to do. I do not go in and do a total hypophysectomy. Instead, I will go to adjuvant radiation, typically with Gamma Knife. If I had only done a adenoidectomy at that initial surgery, then I will go back explore, and likely do a subtotal hypophysectomy, removing this tissue. What about the setting of recurrence in Cushing's? Well, if this was the original MRI, at original surgery sitting here, somebody gets remission and then recurs, then the recurrence is always going to be, where the tumor originally was. So I look and look at the MRIs and say, well, has there been a change? And obviously here, there was a small amount of tissue here, that then grew over time. Well, that invariably is going to be the tumor. And I will offer surgery in that setting, because what surgery at least provides a chance of, is a rapid reduction of the cortisol levels, even if ultimately somebody is going to need Gamma Knife radiosurgery, Gamma Knife takes on average about 13 months to produce a biochemical remission and surgery can get them there in one day. There are indications to remove the cavernous sinus wall, so that if at that, repeat surgery or at the original surgery it is obvious that tumor is adherent to the cavernous sinus wall, then you can watch the video that Ed Oldfield put out in removing how he would remove the cavernous sinus wall. Essentially he would place gel foam into the cavernous sinus to create distance between the carotid and the tumor in the cavernous sinus wall, but also to stop bleeding from the cavernous sinus and then progressively in a stepwise fashion, sharply cut the cavernous sinus wall, attempting to remove the tumor in one piece. Juan Fernandez Miranda also has a beautiful video out, describing his technique in great detail, and I'd encourage you all to look at those. A number of people ask, is there evidence of superiority of the endoscopic approach to the microscopic. I'm happy to talk about that more, but after watching Ed Oldfield for years, I would say that there's absolutely no advantage of the endoscopic approach for the resection of microadenoma over the microscopic approach. And it really should be done by using the technique you're most comfortable with. I have never seen an endoscopic video however, of a resection of a microadenoma that was quite as beautiful as a what Ed Field would do on a routine basis. How do we do with Cushing's? Well, I published my early series of Cushing's, using the endoscopic approach and the results are fine. They are worse with MRI negative, than when you have a surgical target. And I don't think that this is significantly different than other published series. I would say in conclusion, though that the time to get a remission is at that first surgery, I would emphasize that VIBE sequences, and I only get dynamic imaging if the VIBE sequences are negative. And I would emphasize that you should do those on a separate MRIs, not on the same one. The pseudocapsular resection I'm confident, is the way that these tumors should be removed. And you should look at cortisol levels while in hospital and check them on a serial basis because how quickly profoundly they go down is predictive of recurrence in the future. How about acromegaly? So we're going to switch gears a little bit, unless there are questions. In acromegaly, there are some tumors that are microadenomas, and I would say that for those, they should be treated just as we treat ACTH adenoma, that those you should try to remove them in one piece and do a selective adenomectomy using the pseudocapsule. Many are not microadenomas though and most of the patients who have acromegaly, who I treat have macroadenomas. And how can those be removed, and is there something that we can apply that we've learned from the resection of small tumors using the pseudocapsule to removing larger tumors? Marvin Burke Snyder a few weeks ago, gave a terrific lecture of his experience using the pseudocapsular technique for the resection of pituitary macroadenomas, showed beautiful videos, I'd also encourage you to go back in the Atlas and review Marvin Burke Snyder's talk, which I very much enjoyed and learned a lot from. So I'll go through the different techniques that I use in removing these larger tumors. I think that I'll simply show a case at the end, for which I think there aren't perfect answers and would love to hear people's opinions of what to do. So the most standard way that all of us remove tumors when we're not removing a tumor using the pseudocapsule is to remove it in a piecemeal fashion, doing it in a sequential way. First removing the floor, then removing the sides and last removing the top. And I showed this arrow going in this direction for the top, because what we will want to do is to remove it from back to front, but really this four is broken into four, A, B, and C, because really you don't remove this, before you have gone to the top, removed the top edge back to front, this edge, back to front, and then finally the middle, back to front. If you remove the middle front and top, front to back, you're gonna drop the diaphragm down on you during the operation and the rest of the sella remnants are going to be hidden to you. So this back to front resection side, sides, middle, as last is what I'd recommend. So this is the simplest of all tumors. If you could start that video, right. So it wouldn't matter if you did the exact sequences on this tumor, it's soft, it's not very big. And if every pituitary tumor was this easy, there would be no reason to have a lot of lectures on pituitary surgery, because we would all have this figured out. So this is simply removing it in a piecemeal fashion, diaphragm coming into view, of course not using the pseudocapsular technique. This is a piecemeal resection. The endoscope is awfully nice in being able to bring it in. You can go to the other nose to get a cross-court view, so that you can get a view of this side. So if you go in the other nose, you get a better view of this corner there. I'll irrigate, then I'll take a one by one pattie and debris the inside. Danny Prevedello likes to use a Q-tip, that he sterilizes and puts in. I'm more handy with a one by one pattie that I sucked dry and then sweep across the inside of the tumor cavity. I like to do that and I find I'm more handy with that. Danny also uses it while he's removing tumor I think he really shows a beautiful resection of that. Next slide. The other nice thing with the endoscope, again if you can start that, is just the fact that when you have a descended diaphragm, it's key to look in this gutter to lift that diaphragm up and look in this region for tumor residual. On this side, the diaphragm is not blocking that gutter. So the gutter is the junction between the diaphragm and the cavernous sinus wall. It's within this gutter that very often tumor will like to hide. When it comes down it's essential to look, lift that diaphragm up, look for tumor residual in that area. Next slide thanks. And then also the endoscope does allow us if there's a hole in the cavernous sinus wall, as there is one here, being able to go into the cavernous sinus, if it's a soft tumor. I like to use my ring curette as a protector of cranial nerves and remove tumor from within the cavernous sinus. Again, this kind of piecemeal resection, I think even with functioning tumors, if the more tumor you can remove, the less work that either medical therapy or Gamma Knife radiosurgery is going to need to do. Next slide. So here's an example of a patient who came in with acromegaly, large tumor. The tumor had, you can see here as the sella and the tumor had grown into the sphenoid sinus and down into the clivus remodeling that bone. And at the end of surgery was able to get, thankfully was able to get a good resection. You should note that the tumor had a low Knosp grade and was not invasive of the cavernous sinuses. And the only reason that we were able to get remission here was because there was not cavernous sinus invasion. In the tumor that was within the sphenoid sinus, and going back here was readily accessible and thankfully, we got a good resection. I do think this is an example of something that is better done with an endoscope than a microscope. So what about pseudocapsular resections for macroadenomas? Well, the same principles apply, what you have to know is that there are three layers, three successive layers that you need to get through, before you get to the pseudocapsule. Even with macroadenomas, and you have to tell yourself every time, it is going to be there. Now it isn't always there, but if you've never looked for it, you're never going to find it. And so those three layers are the dura, the pituitary capsule, and the pituitary gland. You need to open the dura, and then after opening the dura know, that you still have the capsule in the pituitary gland to sharply incise so that you can get on top of this onion skin pituitary capsule that is surrounding the tumor here, okay? So if you start the video. So if you look, what Ed Oldfield emphasized was that it doesn't matter how long you take to open the dura, open it carefully. And he would do a cruciate incision in the dura, I like taking a box out. I don't like leaflets falling down on me while I'm operating. So I resect the square of dura. I do send that to pathology to see, is there any dural invasion, at times there is, and sometimes that does influence whether I'm going to recommend a radiation therapy after surgery. So taking it off, what you can see here is that, here is tumor, right? Here is the gland. That's supposed to be a G, sorry about that. That yellow gland, and so there is a junction running here. Well, one might say, "Well, I'm gonna go straight to starting to develop that plane." Don't do that. Take a knife and take that knife, a little bit onto the gland. And you want to sharply cut here and across the top. And what you're cutting through is pituitary capsule, and a little bit of gland to be on top of that pseudocapsule, strongly recommend taking a knife and doing that. Next slide. So here is doing just that. So here is the tumor, here is gland, making that sharp incision through it, through the pituitary capsule, through the gland. And what you're gonna see later is that there's actually gland sitting on top of this. It's not just tumor there. There's gland that's covering it that you don't see, but I will take time to carefully score this, score through the pituitary capsule and the gland. Next slide. Before I then start developing that plane, you start that video, you'll see that I'll start using that. This is a long thin coddle, I have this instrument in my hand most of the time will love one, one end has this spear and the other's a little bit curved. I liked not having to ask for multiple instruments throughout a case and I'm just very used to this one in my hand. So here it's taking a gland off from the face, in this case, I'm now starting to dissect down this right side wall, separating tumor from gland. I've already internally debulked the tumor, and I'm continuing to work this plane, leaving tumor, or leaving gland behind and taking tumor out and progressively dissecting the tumor free. Go to the next slide. This is just another example. If you start that video. So here is a not difficult tumor to remove. It's an intrasellar macroadenoma. I've already made the incision, found that plane here, I'm making a incision to internally debulk the tumor, that allows me to then bring the sides down, trying to maintain that pseudocapsule around the tumor, but you can see a nice distinction between tumor and the gland. When that's removed, you can be confident that, that tumor has been removed. Next slide. So what's the problem in that, that all sounds great and use the pseudocapsule, but the problem is that you don't always find the pseudocapsule at the anterior surface, and I think Dr. Burke Snyder, showed his very honest statistics of how often was he able to remove a tumor where the majority of the resection was using the pseudocapsule, and it's not in every case, but he attempts it in every case and I completely agree with that. So what do you do when you don't find it at the anterior surface? Well, Dr. Oldfield in thinking about it also said, "Well, I might not always find it at the front, but I very often will find it at the posterior aspect of the tumor." And so what he would do is internally debulk the tumor and go all the way to the back, go through the tumor, through the pseudocapsule to find normal gland at the posterior aspect of the sella at the dorsum. So here's a video of Ed Oldfield doing that. So he's internally debulked the tumor, couldn't find it in the front, but here's normal gland. And now he's finding the pseudocapsule behind the tumor. And once he finds an establishes that plane, on all sides, he starts to then remove the sides of the tumor. He will remove this side and this side from back to front. Now he's just left with a cap of tumor across the top, but he has established a pseudocapsule in the back. And then he works to remove that tumor from side to side, separating that tumor from the gland here from the tumor, and rolls that out. What a beautiful dissection. He used a lot of forceps during his cases. That is something that I have found I'm unable to do with an endoscope. The endoscope, because there isn't a retractor in the nose, not allowing you to use a pair of forceps. And he used it brilliantly during his cases. Next slide. So there you can do a combined anterior technique with a posterior technique as Dr. Oldfield described. Again, you must do a careful dural opening, make an incision through the gland, or through the pituitary capsule in the gland to find the pseudocapsule, then do a piecemeal resection of the inferior tumor and establish that posterior pseudocapsular plane in order to connect those two later. So let's see an example of that here. So here's a larger tumor. You can see this, it's not a massive adenoma, but it's also not certainly not small. I have previously found a pseudocapsule in the front, and what I did was I went to the back, established a pseudocapsular plane behind the tumor. Thankfully, this was a firm tumor. Here is gland, here's tumor. And this one's firm, and because it's firm, it's allowing me to maintain that dissection plan. You can see that this is a four-hand technique, this is Spencer Payne holding up the diaphragm to prevent it giving me countertraction, holding it away from me so that what I can do is dissect across the top of the tumor and eventually, I will break in to this posterior pseudocapsular plane that I previously developed. And once you see I'm breaking into it there. So now I've found that pseudocapsular plane that I had previously established. Dissecting it free from the walls. And then eventually, and you can see right, this still has a capsule on it. And coming out of the nose there. And although I inspect, because I use the pseudocapsular technique, I know that I'm not going to be finding a tumor residual. Next slide. So we've looked at our results years ago for our acromegalic patients. It shouldn't be surprising that for microadenomas, the rate of surgical remission was higher than for tumors that are greater than two centimeters. Tumors that are between one and two centimeters, have a mid-range resection. The reason that tumors greater than two centimeters have a lower rate of remission, is that the larger the diameter of the tumor is, the more likely it will be to have cavernous sinus invasion. And if there's cavernous sinus invasion, the Knosp three and certainly four, tumors are less likely to attain remission. I did have the opportunity to compare our results with those of Ed Oldfield and published on those, and what we found was that we found no statistically significant difference in any of our outcomes for any of the pertinent ways that you categorize tumors. The Knosp zero to two, three to four, small and large, all had about the same rate of surgical remission. I would close with on this case, for which I don't think there is a tremendous answer for either the microscope or the endoscope when there's this much tumor that's in the cavernous sinus. Although, as I showed there are times where we can get into the cavernous sinus, either medially or from the front, getting a complete resection of this tumor is not going to be possible and there is going to be some form of debulking to get pressure off that optic chiasm, and debulk the tumor, but medical therapy and potentially some form of radiation or radiosurgery is going to play a role. So in summary for acromegaly, the primary treatment is surgical. You can have excellent outcomes for microadenomas and non-invasive macroadenomas, using either a piecemeal resection, but ideally a pseudocapsular resection, but outcomes and the determinants of them are whether that tumor is invasive or not. That's all, thank you.

- Great lecture. Really enjoyed it, John. It shows really tremendous skill, and I think something that always haunts me with this Cushings diseases is, there are cases where there is actually no pseudocapsule. And obviously when there is a pseudocapsule, it's very nice to use that. And why it's so important, because it's very easy when you do the intracapsular dissection to lose the planes. And when you lose the planes and your visualization is not adequate, it's very easy to leave to a tumor behind and does the drop provide remission for the patient. So if I can ask you how often you don't see a pseudocapsule in a Cushing's disease, and in that case, what would you do?

- So for a once, as I said, once a tomour gets over four millimeters in size. Once you can see it on MRI, and you are confident, you are seeing a tumor, then you should find a pseudocapsule. And whenever I don't find a pseudocapsule, I say, "Ed Oldfield would have." It's something in my technique, I cut too deep and cut through that pseudocapsule when going into the tumor. And so sometimes, right the easiest situation is when that tumor is sitting right at the surface. Right, and of course, that's the videos I show, right? Sitting right at the surface and you can cut around it. The harder situation is when there is a real cap of normal glands sitting in front of this tumor that is actually deeper. And what Ed Oldfield did in that situation and what I do, is I don't make a slit through the gland that I separate to find that tumor, cause I can't keep it open. I will take a section of a gland out, because that gland in the end, by the end of the operation is not functional gland anymore. The amount that you've manipulated it, it's not gonna work. And so I will take a square of that gland off to uncover that tumor. And I'd encourage people to give that a shot. You just, and I will take it off a layer at a time so that I don't go too deep and go into the tumor. And but if you do that, you'll much more often find it. And again, when I break into the tumor and have not established that pseudocapsular plane, the next move at the very end of the operation is to go in search of that pseudocapsule and say, no, it really should have been there, let me find it. And that's why I showed that video of my complete failure of taking out, where I should have with the pseudocapsule, but then going back, making a purposeful incision in the gland and finding it. And indeed it was there.

- I respect that. I think part of the challenge is that, if you're not extracapsular and removing the Cushing and you get into a capsular for various reasons, which happens obviously to people like you and Oldfield, is that part of the pituitary can blanch when you put pressure on it, part of the pituitary can look abnormal. And when pseudo-Cushing's patients, specially things can get very infiltrative, based on what I have run into. And in those cases, it becomes very challenging to know where to stop. And I think that's where really the ultimate challenge of Cushing's disease surgery resides, is if you don't have a capsular or you can't find it, and you're working within a pituitary gland that the tumor blanches, and it looks like a tumor as it blanches, it looks yellow because it's not perfusing with flood. When would you stop, then? I think that is the operative challenge that I think, often many of us will interface and have a hard time to deal with. Do you have any thoughts there, John?

- I do. So I have a particularly for tumors, that were relatively small on preoperative imaging. I will have a very low index to do a subtotal hypophysectomy and Kevin Lillehei published his results on that, within the last couple of years and I'd love to know his thoughts about that. But you know, Cushing'ss is such a difficult disease and I very much want to obtain remission at that first surgery. I don't want to do a second-look surgery. I wanna take care of it then. And so if I'm not confident that either as I'm working, you know, I started off confident that I'm working on a tumor, then as I'm working, I'm starting to say, "Wait a second, maybe this wasn't." Then I have a low index to search more, but very often ended up doing a subtotal hypophysectomy.

- Right. I agree with you. The first chance is the best chance at cure. There is no disease process except Cushing that demonstrates that, as like other brain tumors. Let me ask you this question, which is always in an enigma for me, there is a reasonable percentage of patients, who underwent extracapsular resection by Oldfield. The tumor was removed on block, but they still were not cured. So how do we rationalize where the tumor is those patients?

- So, most often that situation is a situation where there is dural invasion, that it's a tumor that was lateral, that was actually invasive of that cavernous sinus wall. And in that situation, that's one of the reasons why for a tumor that was lateral that was sitting against the cavernous sinus wall, one of his first moves was to go lateral after everything was exposed and before starting to make any incisions, he would mobilize the gland and look along that cavernous sinus wall and say, "Is this tumor adherent, yes or no?" And if by his judgment, it was adherent, he'd say, "Okay, I'm gonna have to resect this cavernous sinus wall at this surgery." And of course it's relying on what you're seeing at the time. And it's possible to feel as though it's not an adherent when in fact it was. But if you look back at his patients, who later developed a recurrence, it very often was that there was adherence to the cavernous sinus wall, you know. A significant number of those patients and that's why he developed a process for assessing that cavernous sinus wall by his judgment, resecting it, if it looked involved.

- Right. I agree. And that's the exact cancer I've always thought about is that the laterally situated tumors that find access to a dural through a wall are often able to betray any remission.

- Even when they're small it's like they're a unique tumor because other small tumors, we don't think they can stick to the cavernous sinus wall and invade them as early, something about Cushing's it seems that they're much, even when they're tiny tumors like to stick to the cavernous sinus wall.

- I agree, I bet there is a molecular basis to that, which we still don't know, about Cushing's tumors that are in that environment versus those that are not and how they act, but that's something not known yet. One of the last comments I'll wanna make John is that I think Cushing's disease as you very well described is a very, very different process and disease than acromegaly, I think acromegaly, the tumors are much more gelatinous. They're much more softer. They're much easier differentiated from the regular pituitary and appear to be much more delineated. And it's much easier in my opinion, to achieve a remission. And in fact, even if you don't stay pseudocapsule, which we recommend you do, if you can, the rate of remission is much higher. So I think that phenomenon by itself is a major blessing, for us to be able to cure acromegalic patients. Don't you agree, John?

- I do it's with patients who have acromegaly, there are select patients who have inefficient tumors that you can have gross tumor on postoperative imaging, and they meet every criteria for biochemical remission. They're random growth hormone is less than one, they're suppressed nadir growth hormone on OGTT is less than 0.4 and they have a normal IGF-1, and yet there can be visible residual tumor, and that would never happen in Cushing's. So yeah, the situation of acromegaly has its own nuances, but you're right. We have more options in the treatment of those patients than patients who have Cushing's.

- I agree with you, any enclosure. I think it's just about what to do when you're there and not about how you get there. It's not about endoscopic, you know, microscopic, sublabial, you know, transseptal or you know, endoscopic assisted procedure that are important. I think it's about how you get there. It's about what to do when you were there in terms of dissecting the tumor. I think the endoscope provides such a beautiful panoramic view that gives you an ability to take risks that you often did not take, and with your resection maneuvers, in terms of looking around the gutters, which you beautifully mentioned, but also at the same time can compromise the degrees of freedom that as you see Old Field very nicely used, those forceps had plenty of space and the working angles are so much wider and free, and therefore he can move around and remove those capsules. However, I do believe that the endoscopic crowd is an excellent way to go. As long as you can learn how to use those techniques to increase, your degrees of freedom, avoid sorted. You mentioned that you have to change the nostril. You have to potentially have the suction and endoscope in one nostril, and use the dissector in the other nostril. So you don't have two instruments in the same naris that's doing the fine dissection. I think with those techniques, one should be able to have an excellent freedom angle to remove the capsule. Do you have any pearls of technique, otherwise, John, in expanding your operative corridor angles via scopic crowds?

- Well, I think some of those principles apply with any pituitary surgery, which include getting as wide of a bony opening as you can so that you can, so as you're retracting, you aren't limited by bone so that you can retract enough so that you can see. So, maximizing bone opening is, I think one of the answers creating a large enough sphenoidotomy, so that you're not limited is also one of the important aspects. Don't do the endoscopic approach, trying to do a less invasive approach than the microscope, if that is in your mind, and it wasn't my mind at the beginning of my career, it hurt me. As it turns out, I think that you have to do a larger sphenoidotomy when using the endoscope then when using a microscope and because you're having to make room for an extra instrument and that extra instrument is the endoscope. And so I would say that just in generalities, that if the advantage of the endoscope is the panoramic view, being able to see to the side, but your pathology is right in the middle, meaning a microadenoma, the advantage of the panoramic view, stops becoming as significant, so that the advantage of a microscope with a speculum in place, if you're done using a sublabial technique, well, that gives you the widest with a microscope, the widest exposure, if you're doing it sublabial and you have no restrictions to movement. And if your tumor is directly in front of you, there is at least an argument that, that's a better technique depending on the person. Right, so that if you had given Ed Oldfield an endoscope, he would not have done as well, but that's because he was great with the microscope. And now it's been so many years, although I trained with the microscope, it's been so many years that I've used the endoscope, that in spite of me seeing the advantage of the microscope for Cushing's for small tumors, I would do a better job with the endoscope than the microscope. So it does matter what you do matters less what visualization tool you use, but there are advantages and disadvantages of each, you know, it's not like one technique has it all.

- Very well said. You know, often the minimally invasive or endoscopic techniques are used as a marketing stunt without necessarily a value proposition that is well assessed, especially in neurosurgery. So I think it is so critical and one can argue that, whatever approach you're comfortable with, that's the approach you should use. Just because you have the endoscope, doesn't mean you're better. There's no way about that. In fact, I would argue that the intra-nasal trauma with an endoscopic approach is more than a transseptal approach. And in fact, one can argue that the microscopic approach is superior for microadenoma, especially if they're in the middle of the clan, because just like you said, the panoramic view is not really necessary. These are small, these are focused tumors and the freedom of motion and visualization just in the middle are so critical and you can avoid any intra-nasal trauma and potentially other aspects related to the endoscope. So I think the one thing that I've always learned in neurosurgery, that it takes a lot of younger neurosurgeons to learn, is that when something is new, it automatically means it's better. That's not the case. You have to evaluate the indications, you have to evaluate the shortcomings. And just because you're younger neurosurgeons and you're using a new tool and your older colleagues are using the older tool, you can use that as a method to claim superiority. I think that's something very, very difficult for younger neurosurgery to realize, that neurosurgery, there's so much finesse arts involved with it, that throwing more technology at it, does not mean you're better. There's so many other variables. There's so many pieces in this puzzle. And that's why I always say, when we review papers for general neurosurgery, which I'm sure you do a lot as well, which we appreciate is that just because you have a new technique and you've done a lot of patients, doesn't mean that technique is better, until it's a well-assessed with number of different surgeons, different scenarios, and are projectively assessed. Those are such difficult things to do in neurosurgery. It takes a long time to achieve, but it's something that remember that a new technology does not always relate to better surgery. Don't you agree?

- I do, I do. Well, you know, I had the blessing of working with people who were significantly better than me, right? With Ed Oldfield and Ed Laws, and so who I admired very much and who were my mentors, and seeing how they work, and Ed Oldfield, of course, continuing with the microscope throughout his career. I think there was daily examples of what a superior surgeon he was. And so I just see my role as well, let's see if with the endoscope, I can get it, as do it as well as he can. And one day I may have a video that looks as beautiful as those earlier videos. I saw one by Nelson Oyesiku, that was awfully close using the endoscope. But I haven't had one that looks quite as beautiful, as Ed Oldfield. But I'm not young, I still have some years yet to do it, to give it a shot.

- You know, John, you were being very humble. I think you, your family, dad have really truly given us a huge legacy of excellence. God bless your dad's soul. During the time of the holidays, I know we all miss him. And I think we missed out to Ed Oldfields. I think both of those were giants in neurosurgery who were really amazing, who were our mentors, who we follow their footsteps. Even for me, who unfortunately had a chance to work with them. And I think we have to give those great legends, such a huge credit, unfortunately new neurosurgeons and the mentalities that they have is very different than let's just look, something we can do forward and just throw technology at it, And that makes us better. And if we do anything that our legends did that may not be cutting edge, I think that's a major error. That's a trap. That's something that would affect patient outcomes. I think we have to give credit to our legends, as you have done and know that what they have established are so critical in our success. And just like Isaac Newton said, and I never forget this, that we sure stand on the shoulder of giants. Ed Oldfield, John Jane, Ed Laws, all of those people who truly established transsphenoidal surgery in the modern era after being credited for what they have done for us.

- Yeah, I agree. So with that in mind, I wanna again thank you again for being here with us during this Christmas holiday and John, a huge respect for your career. I followed your career with immense interest and I look forward to having you with us again and also look forward to learning from you more.

- Wonderful, thank you so much. Thank you all.

- Thank you. God bless you.

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