Well, good morning, everybody. We are literally, I think, about 30 seconds before the official start time, so welcome to this session, which is based around management of non-secretory pituitary adenomas, or pituitary tumors more generally, when surgery fails. So I'm Mark Gunnell from the University of Cambridge. I'm rather hoping that we'll have an interactive session. First thing I need to say is thank you and congratulations for staying the course and still being here on the final morning. So the reward is for plenty of interaction, please. For interaction purposes, you've got your polling, but also if you do want to ask a question, please feel free to nip up to the microphone. The session is being recorded, so it's really helpful if you can go there and add that, otherwise the folk more remotely or listening to the recording afterwards won't hear the question. I'll try to repeat them if I can think ahead. So with no further ado, we'll get started. And hopefully you've had a chance to scan that in. I'll just pause a moment just to give you a minute to make sure you have that information. Okay, you can just about see the wall of phones go down. Everybody had a chance? Okay. Okay, so we will move on. So the session talks about when surgery fails, but I thought we ought to get one or two points of clarification in beforehand. And I guess the first question is, what do you mean by fail? And that can mean very different things depending on the patient in front of you, but also personally from a clinician's perspective. Now at a simple dictionary definition, it's pretty much not achieving the goal that you set yourself, which then begs the next question, what actually is failure when it comes to a non-secretory or non-functioning pituitary tumor? So for me, these tend to come into several broad categories. The first is that we are trying to protect, perhaps stabilize, or if we're lucky, rescue the patient's vision. Be nice to preserve, or if we can, recover pituitary function. Ideally, limit the number of adjunctive therapies that that patient's going to need, because every single one of those is likely to have an extra hit in terms of morbidity and potential normal pituitary function. And then, as always, and it's pretty clear that we need to remember that whatever we do has to be an agreeable plan from the perspective of the patient moving forward. So this is probably one of the most important take-home slides on this. These are the things that when you are facing a patient who has either residual or recurrent tumor that I would strongly recommend that you stop and make a list of saying, have I got this information to hand? Because any decision that you're about to make really needs all of this information or as much of this information as possible to be able to make the most informed decision. So the first thing is, do you have access to all the imaging? It's not unusual for people to travel, to come to different centers, and all the original imaging may not be there. And actually, if you do not know what things looked like before you started, you may make some false judgments about what you're actually aiming to achieve, and indeed whether, actually, the first round of treatment has indeed failed. What about the operative findings? It's amazing how few people drag out the operative note and actually read what the surgeon wrote. Actually, how difficult was this surgery? How easy was the approach? What did they encounter? Did they have any consequences in terms of complications? What does the pathology show? The pathology is now getting much more diverse in what is offered to us. So as well as the ordinary H and E stain, is this a pituitary adenoma? We obviously get the hormones, which we've always had, but now we should be getting routinely lineage markers, so the transcription factors SF1, TPIT, PIT1, and also you should be getting an array of indices of proliferation. Now, none of these are perfect. None of these are guaranteed to predict what's going to happen going forward. Usually, they underplay what's likely to happen. But clearly, if there is something worrying in there from the outset, that's something that we need to know about. Obviously, the endocrine status of the patient is critical, but also the non-endocrine status of the patient. So in particular, what are the other morbidities that this patient has? And actually, what age of the patient are we dealing with? Our objectives may be very different in an older patient than they may be in a much younger patient, and we'll show some illustrative cases for those points. What is the local expertise available? We were discussing this yesterday evening, a group of us. I think you should never be afraid to ask somebody else for an opinion. You should never be afraid to refer your patient on to another center that has more expertise to ensure that patient gets the best possible treatment. And then, of course, at the end of that, you better get the patient perspective, because whatever plan you propose, if it's not acceptable to the patient, then it's highly unlikely that we're going to achieve delivery of that. So those are the important things which I think should be on your shopping list to take note of before you start trying to make decisions. This slide just actually also emphasizes that although you probably get a standard set of MR sequences, T1, with and without contrast, T2, there actually are a whole lot of other sequences that are potentially available, which are summarized in this figure here, the reference at the bottom you can easily get access to. And in essence, sometimes some of these other modalities may help to give you important information which might predict, for example, the likelihood of success with further surgery in a specialist center. So it's worth always bearing in mind, do I need some additional specialist imaging information? So with all that in mind, let's get going and let's see how we do with some of the cases. So the first patient is a 44-year-old lady who was referred to us with progressively deteriorating vision. She unfortunately already had compromised vision. She'd had congenital cataracts and pretty much had no useful vision in her right eye. She'd had repeat cataract surgery on the left six months earlier, but there hadn't been any improvement, and that had prompted a look to see if there was anything else going on. She had some hypertension in the background, which was relatively well controlled on the low dose of amlodipine. Nothing much to see on examination, certainly no stigmata of endocrine dysfunction. You can see the left visual field, and that shows that there is evidence, and I apologize, guys, that I'm not pointing at this screen over here. So the pointer, I'm afraid, is going onto this side over here. But you can see there's an upper temporal cut on that left-hand side, and for somebody with one eye only, 6 over 12 vision at a relatively young age. So here are the MRIs for you to have a look at. So you've got T1 with gadolinium, both in the coronal and sagittal plane, and on this occasion, I'm giving you a T2 sequence as well. So I'd like to just pause for a moment and just have a look at those images and see what you think and how that might change your management going forward. Now here's the biochemistry. Now every case you're going to see is going to come the same way. So all the results will be presented in the same way. Anything that, and apologies for reference ranges, which might not be familiar to you, to make it easier to interpret, everything in blue is going to be below the reference range. Everything that subsequently comes in red is above the reference range. So this patient, actually when we met the patient, gave a history of clearly secondary amenorrhea, which was compatible with the galactotrophin pattern we had. And actually there was a biochemical pattern that suggested possible mild central hypothyroidism. You can see the well-preserved 9AM cortisol, proacting normal. So here's your first chance to vote. So this patient's heading to surgery, yeah, unless somebody wants to stand up now and say no. Could be a big person who stands up now and says no. Okay, can't even persuade Professor Levy to stand up at this point. Okay, so this patient's going to surgery. So at that pre-surgery clinic consultation they ask you, okay doc, how confident are you that this operation is the only treatment that I'm going to need? So we're going to go for a like at scale. So everything from not confident at all through to slightly confident. And you've got your chance to vote. Okay, now it's Tuesday morning. It's the end of the meeting. We're all meant to be positive, optimistic, had a really nice time. And there appears to be a monumental outbreak of pessimism. Or maybe it's because you're in a session entitled what to do when surgery fails, which might be giving the game away. Okay, but there could be the odd catch question in here. But it does look like many people are not confident at all. Probably the best we're getting to in reality is somewhat confident. The occasional optimist here. Now, many of you may be answering this question, of course, bearing in mind what your local surgical expertise is and what you think you might be able to achieve. So let's see what happens. So key points that hopefully you noted in relation to this patient. Now, I'm happy if anybody wants to stand up and go to the microphone and tell me what they think are the specific things which are going to influence how we now manage this patient in this particular case. There are one or two signals here that it was important to note. But it's free. We can carry on as it is if nobody feels particularly like they want to move. That's okay. Okay, we'll plug on. So hopefully, all of you would have been thinking about the NOSP grade of the tumor. Okay? We'll return to that in a moment. I don't know how many people were actually interested by the T2 appearance. The T2 appearance here is very interesting. It has some important things to note. Pituitary function tests. That combination of mild central hypothyroidism with a really good preserved cortisol should be raising an alarm bell, should be making you say, hang on a minute, is this truly as non-secretory a tumor as I have been led to believe? And then in this particular patient, we've also got the issue around the fact this patient only has monocular vision. Yeah? So we have got one eye to preserve in a relatively young patient. So that means we're kind of likely want to make sure that we don't put that at risk again going forward. So just to remind you, I'm sure you're very familiar with this. When I look at a patient scan with a non-functioning pituitary adenoma in detail, I'm not going to go into the details of a non-functioning pituitary adenoma indeed for any macro adenoma. I'm always asking myself, where is the chiasm? Can I see the residual normal gland? What is the extent of paracellar extension? So this is a really nice case to illustrate this. So again, hopefully you can now see the chiasm is unfortunately absolutely squeezed at the top here. So there's no room for maneuver or for that chiasm to breathe. Where is the normal gland? Well, you know, it's probably likely to be superiorly. And probably your best guesstimate here is the fact that there is an enhancing area, which is slightly more enhancing on the northern edge. But you couldn't be sure about this on this particular image alone. But that actually is where the normal gland turned out to be, as I'll show you in a moment. Then what about the cavernous sinus extension? So again, we've seen this at many times at the meeting. This is the NOS grading and classification. And this is all premised around understanding where the tumor is in relation to three tangents, which are themselves linked to the location of the intracavernous carotid artery and the supracavernous carotid artery. And you can draw a medial tangent, a mid-tangent through the middle, and a lateral tangent. And depending on how far that tumor goes depends on how far it's deemed to have extended into or potentially invaded the cavernous sinus. So if you now apply those tangents to our patient, so the medial, the mid, and the lateral, hopefully you'll have just noticed there's a bit of tumor poking through. So this tumor is probably a NOSP3A tumor. Now that does not mean that this is not resectable completely, but it does mean that it needs a surgeon who is comfortable and familiar with exploring into the cavernous sinus if you are going to get this piece out. But it may well come out. It may well be something that can be resected. You will only know when you get there. And then the other thing that the astute amongst you would have spotted is the appearance on T2. This tumor contains a number of cysts, both macrocysts and microcysts, and a number of papers, this was actually the very first paper which is now eight years ago to report this phenomena, actually is a potential predictor that this is going to be a corticotrophic tumor. And actually they looked at the presence of both micro and macrocysts or a combination of the two in silent corticotrophic tumors, overt corticotrophic tumors, but also non-functioning adenomas. And so whilst there is no absolute clear separation, you can see that some non-functioning adenomas will contain both micro and more likely macrocysts, and there were certainly macrocysts in this case, actually you should be worried about the possibility of a corticotrophic tumor if you see that appearance on T2. And don't forget that very preserved cortisol level that we saw despite the apparent tendency to central hypothyroidism. So what did the surgeon find? Well, it was largely predominantly soft tumor. Richard commented that he had achieved a gross total resection. He didn't comment on the position of the gland on this occasion, which I'd normally expect him to do. And here is a pathology. You're always going to see this in the same way. We're going to show you anything that's positive on hormonal immunohistochemistry, what is positive on the lineage markers, and then you'll get the various markers, MIB1, which is the antibody against QE67, P53, and whether there are any mitoses. And this all looks pretty standard. It looks like a gonadotrophinoma without too much going on in the way of proliferation, that MIB1 just coming in under 3%, although 3% is probably the threshold for being a bit more concerned. So here is the postoperative imaging on that patient. The patient now has a slight improvement in visual acuity. The field is now normal. And we still have postoperatively the evidence of the central hypogonadism. Interestingly, the thyroid function has actually now gone back to normal. And we haven't dynamically tested at this stage, but maybe we do have an element of GH deficiency, which we may have had beforehand. Of course, we hadn't done the testing for that, and as we know, normal IGF1 doesn't exclude. So just to show you, that's what things looked like pre-surgery. That's what things now look like post-surgery. So with all that in mind, the patient now comes back to clinic and says, okay, how confident are you now that the tumor has been removed and I won't need any more treatment? So the question is, how more optimistic are you now five minutes later after the surgery? I think if my name was Boris Johnson I would take this is a ringing endorsement of my policies and say that this is a totally convincing vindication of the approach and therefore there's no doubt but it does look as if we're still not so sure it looks as if we might have nudged a fraction up but again we are sitting in a session that's all about what happens when surgery doesn't succeed or maybe not so I guess that means that most of you are now thinking about what else are we going to do for this patient so that's the question I asked you how confident are you now so now I'll show you the subsequent slides now we're not going to vote on each of these but it'll be interesting to see if anybody wants to indicate that they would become more confident as this progresses so all I'm looking for is a show of hands that'll just tell me whether you are actually now feeling more confident as you see the follow-up sequence of MR so this is now the appearance at 12 months who's feeling more confident wow you really do take some moving don't you okay so that was one to one or two possible hands so we're still okay at 24 months anybody more confident anybody less confident okay there is definitely a trend towards the this isn't going quite the way we wanted to so we ask the question again and now it's 36 months you don't need too much convincing that unfortunately this tumor has recurred and actually I think most people probably were looking at this saying well I'm not really sure but it actually there are some reassuring features in here you have the hypo density in the middle post contrast but by here it just has that sense that that piece at the top above the carotid is definitely a bit bigger and obviously it's gone on to progress now the patient was actually quite keen just to observe through these phases but actually was persuaded at this point hang on this is not the time now to continue to wait we want to get on and not be facing such a big tumor so in actual fact this patient went on to repeat transfer model which is an approach we commonly use to debolt the tumor down to the smallest possible remnant and then actually went on to a junctive radiotherapy pretty quickly afterwards although we could have paused again it doesn't really make much sense to pause on the radiotherapy at that stage now there are other treatment options we could pursue and they will come up in subsequent cases but an important question which is a particular interest to us because of a program we have in other imaging strategies is could we have better predicted here and here that this was definitely going to happen is there anything else we could have done from an imaging perspective and actually this is just to raise the prospect that molecular imaging could have a role to play in these this is not an area that we have explored too much at the moment but we have a program looking at molecular imaging in particular using these traces here which are amino acid uptake traces which are actually taken up by all pituitary adenoma subtypes and they are what the work we've done in the work that others have done have been mainly focused on functioning tumors but at the end of the day pretty much all pituitary adenomas even when they're technically non secretion on functioning if you look at what you what they're actually putting out for example in a culture dish then most of them are making peptides so most of them will take these traces up and so there we were at six months could we have predicted that something was going on well we added a bit more imaging this is volumetric sequences these are one millimeter sequences this is something called gradient echo MRI this allows you to get much finer detail it does have a for example blur the carotids because you've actually got about one-third of the data set in here with each one millimeter slice thickness actually this probably did have some interesting findings as it does show absolutely no contrast enhancement here but equally you probably argue there's not much contrast in here and here but actually because this patient was in a study we did have the pet data on this patient and this gave the game away that there was already tumor here but it also told us exactly where the tumor is so this white arrow denotes tracer up taking normal gland you can tell where the normal gland is because that's where the stalk is heading so this is normal gland this is normal uptaken nasopharynx but this tumor was already very clearly still there in the immediate post-operative period so in actual fact we probably if the patient would have gone with it would have actually offered her further earlier intervention probably repeat surgery still actually and followed by radiotherapy so molecular imaging I think is a potential route that has yet to be explored in non-functioning tumors could it predict at a much earlier stage those which are likely to be a problem versus those that we can be much more relaxed about follow-up in so I don't know what you guys do but we have a pretty much one size fits all with a few flexions and adaptions depending on what the patient is looking like but we tend to scan at regular intervals which are pretty predicted by an algorithm and I'm not convinced that that's necessary for all patients some patients mean need more imaging some less okay let's move on to a second case yeah please do yeah did you all I mean gone just shout it out and then I can repeat it yeah I probably went past it a bit quickly but essentially the patient's acuity improved and the visual field normalized so in actual fact although we didn't get to 6-6 vision we got to 6-9 but with somebody with a congenital cataract in the background that's pretty good and actually that was definitely worth hanging on to and that's why we were keen to intervene again slightly earlier rather than running the risk of this getting bigger and bigger and as not then succeeding as well second time round thank you okay so case number two was a 75 year old gentleman who had actually been on holiday and he was admitted to a medical center overseas with a collapse he was found to be very hyponatremic he'd actually had an MR brain done that had identified a pituitary mass he was actually managed with sodium tablets and then popped on the plane home which seemed to be perfectly reasonable and that he got there without any untoward effects he had no stigmata of endocrine dysfunction and you probably would say not only are his visual acuity is slightly down but he probably has the earliest signs of a cut in the upper quadrant temporarily on both sides although there was a little bit of drift across that nasal field but as we know that's sometimes all about the technique of the patient doing the visual field test but this is the lesion that was present so he has a on non-contrast we can see a lesion in the cellar with a significant supercellar extension up against the chiasm and actually looking a little bit more northerly on that sagittal imaging and it looks like the the team locally may have actually had some results on which they decided not to give any hydrocortisone although I think probably most people here probably would have done that in a hyponatremic patient in whom they discovered a pituitary mass prolactin was marginally elevated he clearly had central hypogonadism and he also looked like he had central hypothyroidism and again that combination if you don't know anything to begin with that apparent preservation again should at least make you just stop for a moment and think is there any chance that this is actually a corticotrophic tumor that nobody has spotted at this stage not every single one of these patients obviously comes through the door looking like they've got Cushing's so that's how things appeared so in the center the patient was in at that first point he went to theater we don't have the operative notes from that original operation which we haven't been able to retrieve but we have been able to get aspects of the pathology this was indeed not staying for any of the hormones no transcription factor markers had been done but actually the proliferation markers were pretty uninspiring and it was reported at least as being a typical pituitary adenoma so here are the post-surgery images and this is the point the patient was referred on to us so there's your post-surgery his vision actually is now with a stable visual field so there is a depending on which day you do this he looks like you may or may not have a slight cut at the top so probably nothing significant and you'd probably argue given that the chiasm looks like it's clear that's probably not highly relevant and then endocrinologically he's got normal thyroid status he now unfortunately does appear to have been rendered hypo adrenal he's got hypergonadism which is pretty marked still and he's almost certainly GH deficient as well so this point he's referred to us and we're asked the question what else or what more would we now recommend in this patient at this stage so you can answer your own view as to whether you think this is a surgical failure or not you could argue that it's definitely got residual disease but equally you can observe the fact that it's clearly smaller than it was and clearly the vision is now okay so let's imagine the patient sitting in front of you instead of front of me saying okay I've come for a second opinion please what I need to know is do I need to have more treatment now and what would you recommend so with the information that you have to hand would you recommend that he starts dopamine agonist probably cabergoline that he goes for fractionated radiotherapy that he has repeat transomoidal surgery that he goes for stereotactic radiosurgery or would you actually recommend that he stays with surveillance so we'll open the poll well that's very interesting because actually that's many more people perhaps going for surveillance than I had perhaps anticipated but that's quite a large number of people are quite happy at the moment to stay where they are and this patient has come with a pretty open mind he's asking genuinely for a second opinion so there are a small number of people recommending further intervention with transomoidal surgery some for dopamine agonist and not many for radiotherapy of whatever flavor so I'm not going to show you sequentially what happens so this is the pre-surgery imaging that's the post-surgery showed you and you can see his visual fields stable was probably the correct word this is now the appearance of 18 months who thinks that that tumor is now progressing so that's probably about a third of the audience indicating they think it is who would actually now do something different at this point okay a third of you put your hand up say it's progressing but most of you are saying probably not okay this is now three years who thinks the tumors progressing okay so that's now getting probably about 40% of the audience who actually at this stage is going to recommend different treatments or recommend some treatment okay so that's actually not all that 40% by any stretch again we're probably looking at the minority of people still wanting to offer more treatment just out of interest can have a show of hands for those who will be recommending more surgery at this stage those offering radiotherapy at this stage those offering dopamine agonist okay anybody anything else okay so it's more surgery if it's anything patient said actually thank you very much but no I'm just fine as I am thank you very much I don't want any anything else at this stage what about functional imaging so functional imaging could be done but I'm pretty sure here we're just confirmed that this is all very hot and that there has been a small but definite progressive increase in size but please note vision remains completely fine this patient is reasonably happy with his current level of endocrine replacement therapy so I'm going to cut out all the scans in between and show you that over the next eight years that was the sum total of the further progression of this disease and in fact this is the latest scan from earlier than this year who thinks that this patient should have more treatment so that's probably still around about a third of the audience which means that two-thirds of the audience either don't want to give more treatment or have lost the will to live and are waiting for coffee or possibly actually decided that no more treatment well the key thing here is that we were talking to this patient constantly all the time explaining everything to him and you may have lost sight of the fact that he is now 86 he's no longer driving and I'm fine doctor I don't want anything else thank you very much and my vision is just okay and by the way I've got prostate cancer and it's actually something which I'm also deciding to manage in a fairly conservative way now clearly this is all about personal decision-making clearly you could have justified intervening at different stages but you have to bear in mind that not everything that is progressing is necessarily causing the patient a problem and at the moment this remains a radiological problem it is as yet not a clinical problem for the patient now he may pitch up in the next few years saying my vision is going but we've had that conversation and he says if it happens that's fine my vision will go I'm perfectly happy to live with that so I think it's important that we just always bear in mind that what we as an MDT may think is in the in the right interest of the patient and we were discussing just as many as you were putting your hands that we were discussing actively you know we can do a transfer nodal procedure it's not a big procedure etc etc but actually even that statement is an interesting statement because most of us now do it transfer nodals endoscopically and what's the shortest endoscopic operation probably 90 minutes 120 minutes if you still got a microscope you might get it done in under an hour but that's more anesthesia more potential challenges now some people suggested possibly dopamine agonist and actually there isn't a huge amount of data for this we've been discussing this for an awful long time but actually if you do want to read about this this is a really nice paper this is your agreements paper which was published now six years ago this is probably one of the best retrospective data sets we've got these are two centers in Tel Aviv adopting different approaches to patients with non-functioning tumors who had remnants or who developed remnants after first surgery so in one of the centers anybody who was detected to have a possible remnant at the point at which they had their post-op imaging were put onto a dopamine agonist initially bromocryptin in the early days but more latinica berg lean typical doses around about two milligrams a week other patients who didn't have anything and then something became vader visible then went into the remedial treatment group so there was a preventative treatment group now the remedial treatment group get dopamine agonist the first sign that something is actually starting to go wrong and then in the second center they were adopting a conservative approach no dopamine agonist let's watch intervene with surgery and radiotherapy as we need to go so that's how the cohorts were split and you've got roughly twice as many patients down here in the preventative treatment group as a conservative group and then you've got a comparable number to the preventive group in the control arm so really clear about it three treatment approaches conservative early intervention with dopamine agonist the minute you see there's a remnant or intervention when you think that actually a remnant is growing on serial imaging and what did they actually find well actually the datum is reasonably persuasive I mean it's always we have to bear in mind that this is a retrospective study but we're looking at tumor growth in the control group the remedial group where an intervention was coming in later because something had already started to happen versus the preventative treatment group and of course the problem here is always knowing how many of these in the preventive group were going to progress and how many were actually getting treatment they might not have needed but you can certainly see that overall tumor growth is greater in those who are not in the early intervention group again looking at those who actually then needed additional radiotherapy or surgery you can see that far fewer numbers of patients needed those in the prevention group than in the control or residual treatments and perhaps the best way to look at the data is on the Kaplan Meyer tumor progression free survival curves the blue curve here are the people who were having entirely conservative management this is the time to obviously needing an intervention here we've actually got the folk who are actually having a blip and therefore then going on to dopamine agonist and those who are on there from the outset now this is a retrospective study it's pretty much just that two centers together so it has all the caveats and other factors associated with it but it does suggest that there is something in here and yet again we still need really good prospective data to make firm decisions going forward but I don't think this is an unreasonable approach and we did discuss with this patient who is now moving house behind me as you can see we did discuss with this patient that actually dopamine agonist was another option but this is the very time when we're all slightly retreating from dopamine agonist in the prolactinoma field and if you are going to put a 55 year old on dopamine agonist to stop their non-functioning remnant growing that might be 30 40 years worth of management thank you very much so I think we have to still trade of a balance here what's going to be the right way forward for these folk and in case three which I'm not going to show you all the details I'm going to show you exactly why such a study still has a problem we need prospective study this was a lady in her mid 50s no sorry early 60s who had a tumor and you probably be pretty convinced early on that she's got at least the NOS 3b probably a NOS 4 tumor we're never going to get all of that out pretty good surgical result because you can see there is a remnant almost certainly constrained to that cavernous sinus and over six years eight years and ten years of follow-up I don't know maybe it's a fraction bigger that is not a relevant progression on a non-functioning adenoma in a patient who is otherwise well so if we had given this patient cabergoline at the outset we might now be congratulating ourselves on the lack of progression and yet there was none if we'd have given the patient radiotherapy to mop this up we might have congratulated ourselves there's no progression when there never was going to be any progression or at least by this stage to follow so again this highlights the challenges and in particular the discussions you have to have with the patient when you're going to decide whether to go down this path also we mustn't forget and again I'm not going to show you all the details of this this is a gentleman this time that actually repeat surgery can come and it doesn't need to be early it can be later down the line. So this is a patient with a large tumor. That's a decompression, but most of us would think, yep, there's unfortunately still much more tumor there than I'd really like to see post-operatively. Yep, over time it slowly grows, but note the interval. The patient is perfectly well in this intervening period, is uperturatory, and is therefore actually only a radiological recurrence at this stage. And the good news is that with second transphenoidal, the patient then has an appearance at three months where you may say, have we really got it? But the good news is that by the time you get to three years, you can be persuaded that this time, unlike residual tumor here, this is probably, although molecular imaging would help, this is probably now nothing. Now this is timed surgical reintervention, and we shouldn't be afraid in the era of endoscopic surgery with good surgeons of viewing this as a chronic condition that we come back to periodically. We do not need to hit this with everything at the outset, necessarily, and this is all about judging. The ultimate call here is we don't need to intervene just yet because if it's going to grow, it's probably going to grow in an area where the surgeon can get to it, and indeed it does, and then we go back and offer again, okay? Okay, on to another case. So this is a 54-year-old man. He's also actually quite amazingly had a congenital cataract and had visual issues in his left eye. He'd also had a left retinal detachment, and now he had worsening vision. I don't have the fields to show you, unfortunately, but you can see he's down to hand movements in his left eye, and he's got a temporal hemianopia on the right. This is not the sort of tumour that you want to see in MDT. This is a kind of, oh, no, this is not our favourite option. And it's clearly a very big tumour. There's a lot of skull-based involvement likely to be present, and it's way beyond a NOSP4 here, and in fact, if I showed you other slices, it's a NOSP4 on the other side. No surgeon, any surgeon who comes along and tells you, I'm going to resect this whole tumour, should be avoided, and you should go somewhere else. The patient's actually not doing too bad. The clue that this might be gonadotroph in origin is actually the fact that the circulating FSH is slightly high. Actually, Richard said, pretty good decompression, actually. Most of it's soft tumour in the middle. They've got most of the central component out, haven't seen the normal gland. It turns out to be a gonadotroph tumour. It doesn't look particularly exciting on any of the markers. But we went back and reviewed the original imaging, and it just goes to show you need to look really hard. We are now nowhere near the cellar. We are way down in the skull base, and on the CT, you have got clear erosion of bone, which if you saw with a malignant tumour, you'd say that's likely to be metastatic disease in bone. Here, it's not metastasis. It's continuous disease. We could track this tumour all the way down into the skull base, and this is normal uptake in salivary glands on methionine PET, but that is abnormal. We should not be seeing that uptake there. This is tumour here. At this point, this is a different beast. How many people are going to now say, this is okay, I'm not going to do anything? Probably not many of you, because we know we've got all this disease left. I'd actually say that's a pretty good debulking of that tumour to start with, but what you are underestimating is the amount of disease going down here. This patient took quite a bit of persuading that this was not a tumour that we probably are going to want to sit on, but it is technically looking indolent on the markers, but the extent of the disease in the first place suggests it's a bit more than that. In actual fact, he did go to radiotherapy, and actually at the moment, it does look like we've got pretty good reduction in volume, but this is a massive radiotherapy field, a huge radiotherapy field. This is not a patient for stereotactic radiosurgery. This is a patient who needs good old-fashioned fractionated radiotherapy, but this is in to remind me that although in certain countries, and the UK was one of those countries, we used to use a lot of radiotherapy after surgery as an add-on immediately to stop these coming back. Well, we probably don't need to do that in many cases. There are clearly cases where we should not be shy in going for it, and modern radiotherapy, much safer, much better, and all the data about second tumors and about stroke risk we have to remember is based on very historical data from old radiotherapy, where, for example, the dosimetry was nowhere near as good as it is with intensity-modulated image-guided radiotherapy of a modern flavor. Okay, have you still got it in you for a few more cases? Okay, this one is definitely worth waiting for, okay? This is a 10-year-old boy. So this boy is referred with headaches and visual disturbance, which have been going on for three or four months, and he's noticed that he's not managing as well at school, and his vision is starting to fail. He's a prepubescent young man. He's got no overt stigmata. He does not look cushingoid. He's clearly got reduced acuities, and unfortunately he's got a fairly dense bitemporal heminopoeia because he has that in his head. Now this isn't the kind of case that you want to see in MDT, but of course actually these are the kind of cases which really keep you alive. This is something very, very different and something which is going to need all the powers that can be to make sure we get the right outcome in a 10-year-old. So this patient was actually referred to a different center. It was actually in another center at this stage. This is the biochemistry that was available that we managed to retrieve, and apart from the fact that there is clearly a woefully low IGF-1, and it's difficult to make too much of this in terms of his prepubescent status, but it is a truly undetectable test, most of it's actually surprising you're not looking too bad. What are you going to do? Okay, who's going to commit surgery? Not personally, but find somebody who is licensed to do so. Okay, this is good because you are warming up as we get through the cases we're eventually getting to the point where we're getting towards the majority. So most people agree this is going to be surgery. Just out of interest, what approach are you going to take? Who's going to go transphenoidal? Not many takers for transphenoidal. And the reason that you're not going to go transphenoidal, presumably I'm guessing is because you think there's no way we're going to get all this out. We're going to leave a huge amount of tumor in the suprasalar region going north, and there is at least a significant theoretical risk of substantial apoplexy in such remnants. But on the other hand, if you manage to contain that, some people would say sometimes a transphenoidal exploration is not an unreasonable first starting point. Does that mean that most of you are going to go craniotomy then? So this is the operative note. This is an extremely challenging tumor to resect. There is bleeding in lots of areas. It is not safe to proceed. I'm taking a biopsy and then pulling back out. Indeed, the patient had brain swelling afterwards and finished up in the main ICU, pediatric ICU, for several days until he recovered. So at this point, we have made little progress, or maybe we have made some progress, because we actually have the biopsy. The biopsy says this is a pituitary adenoma, but actually this stains diffusely positive for TSH. We don't have proliferation markers. We don't have any other lineage markers. It was a very small sample, but this is a TSH-staining tumor. So over to you guys. What are you going to do now? So this is the point at which I was telephoned and we were asked to discuss at our MDT, because of our interest in TSH-secreting pituitary adenomas. I'd only actually up to this point probably seen about six or seven pediatric cases, because they're obviously not that common generally and certainly not common in pediatrics. So what treatment are you going to recommend at this stage, folk? Are you going to go for dopamine agonist, fractionated radiotherapy, or repeat surgery, somatostatin receptor ligand, or something else? And if it's something else, please do come to the microphone and let us know what you think that might be. Miles, you're off. I missed it, Mark. What was the original thyroid function test? I can't remember what the original T4 and T7 was. Very good question, Miles. Entirely normal, TSH 2.1, free T4 17, which is in sort of middle of the reference range and free T3 upper end, but normal, which is a really good question. So I guess what you're alluding to that, Miles, is you're thinking this is more of a silent thyrotrope tumor because it's not got an association with a biochemical or indeed a clinical presentation of central hypothyroidism. Okay, so let's go for the vote. Okay, so you are about to put this 10-year-old in the hands of somatostatin analogue. Somatostatin analogue is licensed for use in children? Depends on where you are. Okay, this is a 10-year-old. Are you going to treat him with somatostatin analogue forever? No. Okay. Okay, so most people want to go somatostatin analogue. I guess most people... Okay, that might be the phone a friend that's going to give us the answer. Okay, so nobody came up with something else. There was no way on this planet we could persuade this family that this young man should be offered further surgery. They were happy to have him alive. They were still very concerned about all the traumas of the first procedure. How confident would you be that somatostatin analogue is going to shrink this tumor, given that it is just TSH positive, the biochemistry is normal, and he has got no clinical features? Can I have a show of hands? We won't take a vote, but a show of hands, who is confident this is going to shrink the tumor? My goodness, I've returned you to the levels which were even before you came in the room. Total pessimism has broken out. Okay, so if nobody is confident it's going to shrink the tumor, you still think it's worth a go? Okay, and the good news is it's worth a go. Why? Because within six months that's happened, and look at the biochemistry. This makes an important point. Even though it wasn't clear, this patient was actually centrally hypothyroid. Of course, you don't know where his axis normally sits. In actual fact, once you hit those thyrotrophs, that happens, and here we are in our latest scan at the moment. That's where we are currently. This young man has been taken through puberty because he has to be taken through puberty because the rest of the pituitary is not working brilliantly. He is a mid-range dose of somatostatin analog. We started off with the lowest possible dose, titrated it, and at the moment he has, would you believe this, completely normal vision. He's now normal vision. Obviously, he's got significant anterior pituitary failure. The question is, when he gets to an age, and he now is 18, should we now have a discussion with him about trying to retrieve this remnant? When do we get to the point where we say, actually, transphenoidal is now not an unreasonable approach here to see? Because I don't think anybody's ever treated anybody for 80 years with a somatostatin analog, and if he lives to be 90, that's the length of treatment, theoretically, he could be heading towards. But he's done remarkably well. It just reminds us that you need every single piece of information. Even though that surgery sounded like a really bad event, it actually gave us the critical piece of information because I don't think we would have been waving somatostatin analog at him without that information. We have hit pretty much the end of the time. You guys may all need to run away. Anybody who wants to stay, I'm happy to stay a couple of extra minutes and give you one final case. Does anybody want to stay? Anybody interested in staying? Okay. This is my last chance to turn you into optimists, then. I'm just going to check if we have any questions floating potentially online as well. Here goes to the last case. This is a 47-year-old gentleman that we've been looking after for a few years now. He also turned up with progressive visual loss in both eyes. He has gastroesophageal reflux disease, for which he's taking a PPI. Again, very little of notes on the examination, apart from the fact that when he says, my vision's not so good, what he actually means is, I can't really see anything out of that eye at all. It's amazing, isn't it, how long people wait before they come and see you. He's down to counting fingers in one eye. We don't have a field on that side, and we have a temporal heminapia. We've got basically half a field to work with, but that half a field is giving him pretty decent vision. There is the tumour. Endocrinologically at this stage, he's probably just teaching on a central hypothyroid. Here we go again. 9M cortisol looking very, very robust, but we've seen that now in multiple cases which are not corticotrophin origin. He's got a degree of central hypogonadism. At operation, Richard comments, well, this is mainly soft tumour. Interestingly, it is attempting to come down to meet me on the way in, so it's actually into the sphenoid and coming out into the nose. He says, I think I've got a gross total resection. I've seen very good descent of the diaphragm, but I haven't really seen, so he doesn't comment at this stage on where the normal gland is. This turns out, however, to be the corticotrophic tumour. You can probably see where this case is going to head. This one, probably the cortisol, is a bit of a giveaway. Even going back and looking at this guy, it's difficult to persuade yourself that he's definitely Cushingoid. He's T-PIT positive, though. The proliferation markers, as I'm about to show you, confirm the total unhelpfulness that they are in trying to predict how these are going to behave. That is the post-operative imaging. Actually, this guy would do very well to have molecular imaging because it would help us to know the extent of how much of this is post-operative change and how much of this is residual tumour. His vision is stabilised. His visual field, sorry, on the left-hand side improves. He's actually left with a slight cut superiorly, but that's better than he was. Endocrinologically, at this stage, things are not looking too bad, actually. He's still got his central hypergonadism, but not much else. That's where we were beforehand. That's the post-TSS at three months. At 18 months, we're back to that. Now, there is a scan in between, which already shows it on its way, but he was not keen to do anything. By the time we got here, we were able to persuade him, this is really not a good idea. We really haven't got the time to sit. Richard went back and did a second transtenoidal. Again, I'm not showing you all the imaging in between. Richard is an extremely accomplished surgeon. I've persuaded you by now, but when I ring him up and say, have you done the operation yet? He doesn't respond well by saying, of course I've done the operation. Actually, in that small window, we've seen the whole thing regrow to this extent. Obviously, it was debolt and then regrew significantly in between. He said, okay, if you're not very convinced by my abilities transtenoidally, why don't you offer some radiotherapy? We offer radiotherapy, and we this time give a tendency, I don't know what other people do. In these tumors, we tend to give a slightly higher dose. There's no really great evidence base for this. But actually, radiotherapy has a pretty gratifying early effect, in that most people, I think, would believe that this tumor now looks as if there has been significant reduction. And that is sustained, really, for another two years. So at this stage, you're feeling, I don't know how you are in clinic with these patients. I'm always feeling positive, but I'm always being really anxious and trying not to convey too much of my worry, but knowing that this is probably not going to behave itself. And unfortunately, it doesn't, because over the progression, over the next few years, it just slowly gets bigger and bigger. At this point, the patient slightly disappears and then comes back, and he's obviously not very keen about knowing what's about to come down the track. So at this point, Richard says, okay, I think we ought to have a go, because I think there's a lot of intracellular disease that I can get here. So he operates. At this point, he's not talking to me anymore afterwards, because I say, so you've done that same sham operation that you did previously. And he said, okay, well, if you're not convinced by my transphenoidal skills, how about I do a craniotomy? So I say, you're not very good at those either. So not joking, this is a person having significant tumor debolt in between these scans, and this is now the speed at which this tumor is regrowing in between. And of course, the proliferation index, which I'm not showing you, is now high and is now starting to look like those tumors that you are going to get towards calling carcinoma at some point. So what's the answer? Well, the answer lies in the reference at the bottom. What are we going to do next? What have we got left to give this guy? So it's probably temozolomide, isn't it? And that's what we've done. So we're pretty much in the early stages. This is now axial imaging and sagittal imaging to show where this tumor is. ACTH has now become a pretty effective tumor marker for us in this patient, even though he does not have any clinical features of Cushing's and his cortisol dynamics, interestingly, remain totally normal without evidence of Cushing's. And we're in the same boat again. Yes, I'd love to see him in clinic and tell him this is all positive. Yes, we have definitely got a response radiologically and here, but I guess most of you are sitting there feeling very anxious about where this is all going to finish up. And that is in the end of the handout. This is where we now need to get into the novel parts of treatment. And this is not suitable for this patient at this point in time, but there are very interesting potential strategies moving forward with these on the basis of genomics, radiomics, and other things that we and others are interested in pursuing at the moment, and, for example, things such as manipulating the PI3 kinase, AKTM TOR pathways, also looking as a potential interesting place, and his tumor has got seriously deranged PI3 kinase pathway signaling. So I think we're off then into the territories of unknown, unproven approaches, and my last plea is that this is where we need to collaborate with each other. None of us have enough of these cases to be able to solve these on our own. We need to be doing it together. So I'm going to finish at that point. Thank you very much for staying the extra case a few extra minutes. Thank you.

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