Good evening everybody, and welcome to a Thursday night members webinar. My name is Bruce Stevenson and I have the honour and privilege of chairing tonight's webinar. I don't think we have any new members in tonight, so usual rules apply.

Pop the questions into the Q&A box and we'll hold them all over to the end and then we will ask Owen kindly to run through as many of those as what we can. So Owen is an RCVS, an American specialist in veterinary oncology. He's a Cambridge graduate who spent 9 years in practise before his residency term at the Royal Veterinary College.

Since 2017, Owen has worked for Highcroft Referrals in Bristol. He is interested in all aspects of oncology, but especially hematopoietic malignancies, immunotherapy for cancer, and perineoplastic disease. Owen, welcome back to the webinar, vet, and it's over to you.

Great, thanks for the introduction, Bruce, and thank you again to the webinar vet for having me back. I really enjoy doing these evening talks for Webinar vets, and I particularly enjoy talking about mast cell tumours. So that's all good.

Thank you to everyone for tuning in tonight to listen. First, there may be a little bit of deja vu here because some of you may remember that last September I also did a talk on Marcel tumours sponsored by Verbac and that was a review about Marcel tumours in general. Please, don't fear, this webinar will be completely complimentary to that.

I think, and many other oncologists think that one webinar, simply not enough to do mast cell tumours, because they are really, really confusing and very, very challenging things to deal with. So I'm particularly pleased to be doing this webinar. In this one, I'm going to be talking very practically.

About how I navigate the Mar cell tumours that I see in practise. I'm gonna be using examples of the cases that I've treated to talk about which Mar cell tumours we worry about and which ones we don't, and specifically, which treatments I'm gonna use. One thing with mast cell tumours that makes it even more of a challenge is that in principle all the treatments that are commonly available are very, very accessible to the vet in practise, and today I'm going to review how I would use surgery, intralesionaltigates, tiglate rather, steelfonta, chemotherapy, and tyrosine kinase inhibitors.

And just before I start, I'll say that for this webinar, I have no conflicts of interest to disclose and there's no corporate third party sponsorship. Say I hope you all have a glass of wine or beverage of your choice, and we're gonna start by looking at Desmond's penis. This is Desmond, who is an eight year old male neutered chocolate Labrador, and he's got a cutaneous mast cell tumour on his prep use.

We did have, it's now been removed in this photo. The path report described excision as being complete. It was intermediate grade on the patick system.

We've heard all that before, haven't we? Low grade on the pupil system. And it had a kind of middling mitotic activity.

So, I have a question for you guys. What would you do now? This isn't a poll, you don't have to vote.

I'd just like you to think of what you'll do, faced with a tumour like this. You got the option of doing nothing. Staging and then making a decision.

Putting him on TKIs, giving a course of inblasting and red. Staging and then definitely giving some form of medical therapy or to run further prognostic tests. And I guess this question is really asking about which Marcel tumours we're gonna worry about and which ones we're gonna say is OK to leave.

And it highlights just how frustrating mast cell tumours can be to vets. Because all mast cell tumours are cancers, OK? They all have the potential to spread to other parts of the body and bring about tumor-related death.

Some of them are at one end of the spectrum here where they behave as if they're benign lumps, and they choose not to cause a problem. Others of them are rapidly progressive systemic diseases, and it's obvious that they're going to be very nasty, but most of them are cell tumours that you and I see in practise are somewhere in the middle. And we're not talking a definite one thing or another.

We're talking about shades of grey. We're talking about probably, possibly and things like that, and communicating this uncertainty to the client and why you want to base further tests on this and things like that can be a real challenge. So with mast cell tumours, I would encourage you.

To try to categorise them, you take this spectrum and shades of grey. And using probability and real world common sense, you put them into two categories, the high risk ones that you think have a very real chance of causing tumour related death and spreading, or the low risk ones that could still cause tumour related death and could still spread. But just as I could be in a severe car accident when I drive home from work, hopefully, that's very unlikely.

OK? And to place the Marcel tumours in the high risk or the low risk category, we look at the prognostic factors. So I'm just gonna recap over some of the most important prognostic factors that I use in categorising a mast cell tumour.

Number one is the GASP test, OK? If you look at a mast cell tumour across the room and you go. Then that's a bad one.

That's high risk, OK? Mast cell tumours on certain areas of the body also correlate with a higher rate of aggressive behaviour, and this may be of interest here. Mucous membranes, scrotum, perineum, prepus would be key as well as nail beds.

Who trusts this dog? I'm guessing not all of us do trust this dog, and just as we may be a little bit suspicious about Shar Pei's, I think we should never trust a Mar cell tumour on a Shar Pei. This breed alone correlates with a very aggressive Marcel tumour behaviour.

Obvious lymph node metastasis, that's quite a clear one, doesn't require much explanation. However, systemic signs of vasoactive amine release does, OK? Every single mast cell tumour in the world can degranulate and it can cause swelling and ulceration and redness, etc.

However, the ones that are able to degranulate to such an extent that you get systemic issues like this poor dog here, with all this red skin. Are ones that have got to such a huge tumour burden that they've usually metastasized or are usually really, really big. So I guess this is an indirect prognostic indicator.

If there's enough release of vasoactive amines you must have enough cancer cells that you therefore must have a metastatic, huge or very aggressive mast cell. And finally, we shouldn't forget the local recurrences. Because there's a lot of my cell tumours out there that get incompletely removed and that's the end of it.

They never recur. The mast cell tumours that recur after an incomplete excision are in the minority, and that signifies that they are a nastier, more aggressive breed of mast cell tumours. So before anything's removed or biopsied, please consider these things here.

The strongest features that decide whether I worry about a mast cell tumour or not, however, are those on the pathology report. High grades on both the patnick and pupil system is high risk of aggressive behaviour. However, most mast cell tumours are intermediate grade.

Or intermediate on pat nick and low on the pupil, would you agree? Certainly the ones I see are like that. So for these intermediate grade tumours that could be very nasty or could be completely harmless, I would encourage you to look first at the mitotic count.

And if the mitotic count is borderline, I'd encourage you to have a look at the K 67 score. Because these things here have been shown to be very strongly prognostic, completely independent of the tumor's grade and other strong prognostic factors. So these are very powerful things to look at.

And when you're faced with an intermediate grade mat cell tumour, this can help push you one way or another. Labs often offer a lot of other prognostic tests on my cell tumours, and these have also been shown to be significant. But whether they're actually independent or whether these things co-occur with other strong features like high grade.

We're not so sure at the moment. So these are, I guess, less strong. So overall, we have the Mar cell tumour and we have to look at clinical and historical features, and then path pathological features.

Write a list if you need to. And then decide whether there's anything that warrants a high risk designation or not. It can get a little bit blurred because if you look at enough of these things, you'll find something that has correlated with aggressive tumour behaviour and we do have to make a judgement call.

But when, so when we're making a judgement call, it's useful to bear in mind that the strongest features here are the histopathological ones. Whether there's obvious lymph node metastasis. And the mucous membrane location.

So sometimes you might get tumours like, for example, a subcutaneous tumour or a tumour on a distal limb. There are reports of these having a more favourable prognosis than tumours in other areas of the body. However, if it's a high histopathological grade, high chi 67, or obviously metastatic, I think things, these things may override the favourable anatomic location.

But ultimately it is a judgement call, and I think people like me are very happy to give advice if needed. Now I'm going to do a brief digression here because it has always struck me, it's a bit awkward in dealing with a mast cell tumour and that the strongest features on whether you worry about it or not are histopathological. And so you have to give definitive treatments before you find out what they are.

In other words, you have to remove the tumour before you realise whether you, it's a bad one or not. It would be really nice if we could find out on cytology whether we need to worry or not. And so, in the last, I don't know, 1015 years, there have been a few attempts to develop a cytological grading system for our cell tumours, and they've all been quite inaccurate.

This one, however, is reasonably promising, OK. In this system that was quietly published in 2016, it showed really quite good accuracy data in predicting aggressive mast cell tumour behaviour. OK?

Now, 90% sensitivity means that it's gonna miss an aggressive mast cell tumour in every 10 samples you submit. And 94% specificity means it will give you a false positive 1 in 20 tumours that you submit. So it's certainly not perfect, but it's still not bad.

And I'd like to see this being explored further. One of the limitations of this system at the moment is that it's only been evaluated by the authors of this paper who actually devised the system, and we want to see how easily transferable it is to other clinical pathologists. So please ask your clinical pathologists if they can apply the Camus grading system to my cell tumours.

But anyway, I've done enough discussion now, this is a case-based webinar. OK, so we'll come back to question one, this little dog here. What would I do?

Well, the mitotic count was 4. And the cutoff is above 5, OK? But that is for mitosis per 10 high power fields.

And you can imagine that if the pathologist had looked in a couple of different high power fields, they may have got a slightly different answer. So I think this is a little bit too on the fence for me to be happy with. And Chi 67 might be an appropriate test to double check this rate of mitotic activity.

In this case, it came back as high, so it would be classed as a high risk tumour. You could look at this tumour another way though, because it's on the prep use and Mar cell tumor's on the prep use. Have a greater likelihood of metastasis and tumour related death.

So even if the K 67 was low and the histopathology was completely unconcerning, I would still want to offer staging just because of its anatomical location. Now, I've got some slides on staging which I could show at the end, but I wasn't going to go through staging exhaustively now, because I did so in the first webinar from last September, and that's still available to see, free of charge on the webinar that platform. But if anyone's interested, I could go through this all at the end.

Just to say though, if I'm staging a mast cell tumour, I will rely on the fact that mast cell tumours metastasize via the lymphatics. OK. So an easy way of staging mast cell tumours is check out the first port of call in the in the lymphatics, the draining lymph node.

And then check out further down the lymphatic chain before the lymph enters the general circulation, the liver and the spleen. Just like that. Now because mast cell tumours are round cell tumours, just like lymphoma, you can get infiltration or even effacement of an organ that looks completely normal.

So, ultrasound on its own is almost worthless. You're going to need to stick needles in things under the guidance of ultrasound to see whether there's mast cell tumour there or not. But in principle, it's something that can be staged very easily with ultrasonography.

So in our dog Desmond then, the chocolate Labrador with a propecial Marcel tumour. And the H I 67. We did this, we did the staging.

And in the left medial iliac lymph node, we found metastatic mast cell disease. The liver was clear and the spleen was here. OK.

So now we can add to Desmond's list he had a metastatic Marcel tumour. And I have another question for you. What's his prognosis?

Don't you just love it when the owners ask you questions like this? How long's he got? What would you say?

Again, you don't need to vote, there's no wrong or right answer here. I just want to know what kind of, I'd like you to think rather, what kind of thing you'd say. Well, actually, if you have a patnic intermediate grade mast cell tumour that spreads just to the local lymph node and chooses to go no further.

Then there's a very high chance you could cure this. And to be fair, that's a great thing, isn't it? We don't often talk about curing metastatic cancer in veterinary medicine.

Well, you can here. OK? You have to work hard.

You will need to remove or treat with radiotherapy, the primary tumour and the metastatic lymph node, and you'll need a course of chemotherapy, typically blastine and prednisolone afterwards. And I'd love to be able to give you a way of doing that for free. There's quite a cost associated with these things.

But if you do that, You can cure the vast majority of these cases. So when we're looking at mast cell tumours and evaluating whether they've spread or not, I would encourage you not to think about a, a two scenario situation where a tumour has either not spread or it's spread. We talk about the non-metastatic cases, regionally metastatic cases, or the distantly metastatic cases.

Non-metastatic is always good, distantly metastatic, that is to liver and spleen or to lots of other lymph nodes. That's always bad. However regionally metastatic.

Where it spread just to the draining lymph node and no further. That may not be too bad at all. In principle, you could cure these.

Let's talk about treatment now. Now, with mast cell tumours, as we said, about 80% will be cured with local therapy alone. That's because the majority of mast cell tumours are low risk mast cell tumours.

They're all cancers, but for whatever reason, the majority choose not to cause much harm to the dog. And just to be clear here, when I'm talking about local therapy, I'm talking about something that focuses on the tumour area and does not act in the rest of the body. So surgery is a great example.

Radiation therapy is another example. Or now we have intralesional therapies that I'll talk about in a minute. And it's about 80% of our cell tumours that will be low risk, and you can cure these with a local therapy planned appropriately.

Now for the high risk ma cell tumours, you need local therapy and you need systemic therapy because these guys have a high risk of metastasis if it hasn't occurred already. And some of you guys may be thinking, well, actually, if we're gonna give chemo or a drug. Why don't we just do that and not do the local therapy.

And I think that's a very logical thing to think. But actually in a number of publications, and this is just one of those. The dogs who have metastatic or high risk mar cell tumours that that receive local therapy and systemic therapy will do far better than those that just have systemic therapy alone.

Let's talk about some local therapies first then. Surgery is the treatment of choice and it's definitive curative treatment for the majority of more cell tumours. I'm not gonna say too much because we all understand about surgery.

The recommended margins of excision of Marcel tumours is gonna be 2 centimetre lateral margins for most cases, although possibly up to 3 centimetre margins for the nastier or bigger tumours. And one fascial plain deep. Now working in referral practise, I see a lot of cases that people have treated in practise, that have not gone the way they've wanted.

And usually people are very good at getting lateral margins. The quality of the deep margin is often something that suffers. So that's one thing to pay particular attention to.

Have you got a good quality deep margin all the way through the tumour. And now we have a new exciting drug, Tiglinoltiglate Stelfonte. Which is also a local therapy.

And it's injected directly into the tumour, and one injection has been shown to cause complete regression of 75% of our cell tumours. And that rises to almost 90% after two injections. Now bear in mind in this study they were treating all mast cell tumours, not just the low risk ones, they were also treating the really nasty ones as well.

So that's pretty good. After the injection, What you'll find is that you get hemorrhagic necrosis and direct necrolysis or oncolysis of the cancer cells starting within hours, and the tumour drops off, leaving an open wound that heals by second intention. There's lots of clever and interesting ways in which this work, but the key one, I'd like to draw your attention to.

Is the disruption of the tumour vasculature via activation of the protein china C. And Steelfons has now been licenced for about a year, literally almost a year. It's licenced for all grades of Mart cell tumours.

But they have to be non-resectable, non-metastatic. It's licenced for all cutaneous mast cell tumours and for some of the subcutaneous mast cell tumours that are located at or distal to the elbow of the hock. All mat cell tumours must be less than or equal to 8 centimetre cubs in volume.

And they must be accessible to intra tumoral injection. So radiation therapy was previously the other local therapy we could talk about instead of surgery. But that's often very expensive and maybe geographically inaccessible.

So from a practise point of view, we had surgery, and now we've got steel Fonta as another second weapon for the local treatment of our cell tumours. And this brings me on to my 3rd case, my 2nd case rather, 3rd question. Meg is a seven year old female entire golden retriever.

She has a mast cell tumour distal to the right hock that's 3 centimetres in diameter. And a biopsy, it's patn intermediate, pupil low grade, aren't they all? Haven't we heard that before?

And it's also nice low mitotic activity, a long way from the cutoff. So in short, If you bear in mind the prognostic factors I talked about 20 minutes ago, she's got none of these negative prognostic factors. It's just a mast cell tumour in a very awkward location.

I'm sure that we've all seen cases like this, and I'll be interested in your thoughts on how you'd like to treat Meg. The considerations I've put here, one on TKIs. A course of blastine or prednisolone.

Selfonter refer for radiation, or do a more conservative surgery in-house. And actually I think there's an argument behind all of these, but I'll tell you my choice in a minute. The first thing I wanted to say, however.

Is that I tend to get a lot of inquiries about this kind of Marcel tumour and up until recently, the key question people were asking is, can I just put this dog on meitinib, or to serenib? And that would be, I think, my least favoured choice out of these. You see, medical therapy for more cell tumours is never as good as a local therapy.

And this table, I think illustrates that well. Prednisolone, a lot of people are excited about for our cell tumours, but it's only about 1 in 5 that will shrink if you put them on prednisolone. And then you've got the chemotherapies, Lemustine, or vimblastine and prednisolone, and it's kind of as as near as dammit about fifty-fifty.

Half the mast cell tumours ignore the drug and don't change at all. And then you've got very similar stats for the TKIs. So you could put a dog on TKIs, it's only a fifty-fifty chance they're gonna respond.

OK. The in the Marcel tumours that have the CI mutation positivity, there's probably a greater likelihood that they're going to respond to TKIs, but it's only moving the chances up to more like 70 or 80%. And there are some studies in field settings of using TKIs for my cell tumours that have shown that the cases that had the mutation and were no more likely to respond to TKIs and those that didn't.

So there's really a lot of uncertainty in whether a mast cell tumour is actually going to respond to the TKIs. The other thing to bear in mind in using TKIs for dogs is that they're very expensive, OK? This dog's a golden retriever, let's say she's 30 kg.

And these are the costs I've got from an internet pharmacy that I looked up a few weeks ago. In other words, they're probably some of the cheapest costs around. In addition, you're gonna have to see the dog monthly for bloods, blood pressure, urine tests and things.

And by the time a year is out, you've probably spent thousands of pounds and it becomes a lot more expensive than surgery. So for these little mast cell tumours where people are wondering, can we just put them on TKIs well? To sum up, surgery is potentially curative.

TKI is not curative, it's just gonna suppress the Marcel tumour. And so for that reason you can't really stop it, you've just got to keep going. Surgeries, one off.

TKI's ongoing. Surgery is cheaper in the long run. TKIs can get very, very expensive.

Surgery has the normal risks of GA and surgery that we all understand, and TKIs have potential for chronic adverse effects. I have seen dogs who've been on these drugs for years developing some unusual and quite rare phenomenons, things like protein losing nephropathy that doesn't resolve when you cease the drug and stuff like that, vasculitis, stuff like that. So for a low risk mast cell tumour.

Where you think the likelihood of spreading is gonna be very low. Giving a systemic drug is always gonna be second best. And for these reasons alone, the cost and the fact it's ongoing, I would not want to use it in a dog like Meg.

So if you've got a distal limbmar cell tumour or you could scratch out distal limb and put muzzlem cell tumour, complete excision's gonna be difficult. My approach would be to biopsy it first and to stage it first. That's because if I before any treatment, I want to have absolute certainty or as close to that as possible, that this tumour isn't gonna be much trouble.

I want to make absolutely sure it's definitely low risk. Now one thing you could do after you've done that is consider surgery with proportional margins, if it is a low risk tumour. Now proportional margins technique involves surgical excision with lateral margins equal to the maximum tumour diameter.

OK, you still need a fascial plane deep. But you can get away with much less skin removal. And that's not a perfect technique, but it is reasonably reliable.

And if you've got the right clients who you think will forgive you and fully understands that there's a risk that the tumour may grow back and that this isn't the, the gold standard treatment, then there's nothing wrong with it. If you find you've actually got a high risk or metastatic tumour, then you could always consider amputation or a radical procedure. If the Marcel tumour is causing a lot of morbidity, ulceration, itching, swelling of the leg, etc.

But for Meg, I think Stelfonte would be a great treatment as well, and I'll come on to that in a second. Radiation therapy or chemotherapy could also be used. I think radiation's a bit better because it's a local treatment focusing on the tumour, and chemotherapy, which is a whole body treatment.

But neither of them will hit the tumour very hard. One way you could improve the sensitivity to radiation or chemo is to debulk the tumour, OK? That's because in any tissue or any tumour, you have cells in the cell cycle here, or you have cells in the resting phase.

And the proportion that are in the cell cycle is greater, the smaller the size of the tumour. So if you surgically debulk the tumour, you'll shift cells from resting phase into the cell cycle, and you'll make them more sensitive to radiation or chemo. But returning to Meg's case.

I think the proportional margin surgery might be worth considering. Just as the intralesional tiling or tiglates. And I'll tell you more about this.

Because remember I said a minute ago a key mechanism of action is not killing cancer cells as such, excuse me, but disrupting the blood supply to the tumour. And The most exciting thing seems to be that the effect on the blood vessel seems to be specific to tumour vasculature. There have been studies where tigliol tiglate has been injected into normal skin and it causes much less damage.

There's something about the vasculature of a cancer that is much more sensitive to this drug than normal blood vessels. And so, where surgery is very non-specific. Tiglin origlate is a targeted skin sparing treatment, and I think it is potentially very, very useful for these tumours in surgically awkward locations where you can get, I hope, complete tumour clearance.

With a minimal loss of surrounding skin, so this is the just the kind of case where I'd like to use steel fonta. This is a very recent study published about 8 weeks ago, possibly a bit longer. Which looked at the wounds forming after steel fonter is used.

As it's a JVIM article, it's open access. And you're welcome to download this, there'll be no cost associated with it, and you could see these pictures and the descriptions with your own eyes. Further back have also got the promotional material with lots of good pictures too.

This is the typical thing you get. Inject the steelfonta and the tumour drops off and you've got a big hole, looks a bit gory. But actually, in a lot of cases for small tumours, the worst of it's over and done with, within, within about 2 weeks.

By 4 weeks, it's looking really good. You've got bigger or more advanced cases here and some of them do look a bit gory like that one. And I could think that there's some clients who will be OK with that, other clients will completely not be OK with that.

So it might affect the treatment you choose. But again, all of these, after about 28 days, it's not looking too bad at all. And the paper also describes this one, which is a very nasty and diffuse looking tumour.

On a dog's foot. And after the stealthon was injected, a whole load of skin died along the path of the lymphatics. Up to the dog's axilla.

And I guess we could discuss academically whether there was kind of seeding of mast cell tumour along the lymphatics up to the local lymph node or not, or whether this was another completely unrelated effect. But it did look pretty horrible, and then it healed. It healed quite nicely and actually quite swiftly as well.

So some cases may take you by surprise and you may end up with more of a wound than you counted on. But it still healed and I still think it's a very good treatment. And the main thing I like this is because it's specific to the tumour vasculature, and it could be skin sparing.

There we go. It's the final result in that dog. OK.

Excuse me, I've got a bit of a sore throat. So we'll move on to question 4, it's Dustin. Dustin's a staffy.

And like all staffies, he's got another mast cell tumour. He's had them before, but this one is worse than the others. Poorly defined mass, caudal to left scapula, 8 to 10 centimetres in diameter.

A lot of edoema, very erothematous. It was surgically removed and the vet did a great job actually, but it was still incomplete. And sadly, pupil high grade, panic high grade.

OK. Staging was negative. Here's where I'd like you to think what you'd do.

We've got a high grade mast cell tumour incompletely excised, and again I'm gonna give you similar options here. But on TKIs in blasting red, revision surgery, refer for radiation, or monitoring only. Now, I want to clarify what I said earlier.

Like the all, even the high grade mast cell tumours will always do better if they have like local therapy as well as systemic therapy. And that's true. I'm not deviating from that from that.

In Dustin's case, there is a temptation, therefore, to think, let's go for a vision surgery or radiation to consolidate the local control of the tumour. And probably that's the gold standard thing to do. That's probably the very best.

In the real world though, these things have a cost. And they may delay the starting of medical therapy. And I'm not sure the benefit that they'll bring is justifiable.

Well, if it's incompletely excised, we'll assume there are microscopic levels of cancer around the surgical site. But since it's a high grade mast cell tumour, there's probably microscopic traces of cancer in lots of places. So do we focus all our effort and all our funds on targeting the bit at the surgical site?

I think it's gonna be more prudent here to go in with a systemic therapy. Remember, this is much better than the situation would have been if we had this erythematous swollen, edematous mast cell tumour that hadn't received any local therapy at all. I think it's had its local therapy.

It's done about as good as you can, and we need to get the chemo in as fast as possible. So we're talking drugs. And again, people would ask a very good question here.

Should we put on massivets or palladia? Let's explore that further. I'm just gonna review how the tyrosine kinase inhibitors work.

You see, the way that cells are encouraged or told to divide by cell signalling from other cells is when a ligand binds on a receptor. The receptor undergoes various changes that kicks off a cascade of molecules in the cytoplasm. Something will then enter the nucleus and kick off or change the transcription of genes.

This will alter the cell proliferation and cell growth. And that happens every second of every day in all of us, and it's a very appropriate thing. However, in the case of a cancer, particularly a mast cell tumour, you may have a mutated receptor.

Such it doesn't need a ligand binding to it. It'll just keep telling the cell to divide, regardless. It's completely autonomous, it's doing its own thing.

And so, when you the thyrosine kinase inhibitors. Will be blocking the action of these mutated receptors in neoplastic mast cell, in in mast cell tumours, OK, so you don't get the downstream signalling. Not that.

So, the reason why I'm telling you this is because you can see that they're not actually killing cancer cells. Chemotherapy drugs will kill cancer cells. The TKIs will just alter the cancer cells to normalise their behaviour.

And if we look at what that does to the cancer burden, if you're giving chemo, like blastine or lomustine. It will knock down the cancer burden. Before the next dose is given, the cancer burden will start to grow again, but then you give a dose, then it knocks it down again.

Cancer burden starts to grow, dose given, knock it down again, and so forth. And eventually you get to a level where the cancer burden is at such a low level or effectively, theoretically zero, and you can stop treatment. With the TKI drugs, that doesn't really happen, OK?

So you need to just keep giving these in theory, and there's no clearly defined set point when you can stop them. So with with TKI drugs, some people might stop when things are under control. When I've seen that happen, very often the tumour comes back again.

Sometimes you might be lucky and there may have been complex effects of the immune system, that the immune system's controlling the cancer or various other complicated things have happened and helping you out. But often if you stop a TKI it will start coming back. So the chronic use makes them expensive.

And the chronic use also brings up the possibility of, well, the greater likelihood rather of chronic side effects. Let's examine the side effects of the chemotherapy agents and vimblastine is a really well tolerated drug. Very rarely upsets a dog's tummy.

It doesn't have nasty idiosyncratic side effects, none to speak of, really. Myosuppression is the principal side effect. It's not considered to be cumulative.

The dog usually recovers and the white cells recover within about a week or so. So if you need to keep giving it and keep giving it, you can. Now lousine is also myelosuppressive, but variably so from dog to dog, and it does have an unpredictable hepatotoxicity.

Most dogs are fine, but ultimately wear and tear on the liver limits the amount of drug we can give. And in some dogs you can get a very idiosyncratic and severe hepatotoxicity early in treatment. So it's not quite as good.

Here are just some of the effects of TKIs though, OK, lots and lots and lots of them. There's tyrosine kinase receptors in cells all over the body. And to erinib and Mitinib, the two licence drugs we've got a very broad spectrum molecules that inhibit much more than just kits.

So, you can get all sorts of weird and wonderful side effects from TKI drugs. And I think the longer the dogs are on them, the more likely you're likely to see weird and wonderful things happening. And they might not be very easy to diagnose, like muscle cramping has been reported and stuff like that, lameness, depigmentation.

I've seen some really nasty protein leaves in nephropathies. And that is a reasonably common side effect of Taserinib in particular, in the short term. However, the nasty cases I've seen, the dogs have been on it for a few years.

And it's not reversible. You'd think, because this is just a ligand binding to a receptor, that the effect is reversible, and a lot of these side effects are. But some of these chronic things that we see, if they've been on TKIs for ages, seem not to be reversible.

They seem to be permanent. So, coming back to Dustin, my choice would be a discrete course of Vinblastine and prednisolone, OK? It's a discrete course that will bash the cancer burden down towards 0.

I choose vimblastine over Lomustine because the side effect profile's really good. And since it's a course, it's relatively cheap. TKIs are expensive and there's no well-defined stopping point.

They've also not been very well tested or evaluated or licenced in this setting. Now I'm gonna give you another prognosis thought here, OK? Just like our first dog.

So if Dustin's owner turned to you and say, and said that awful, really annoying question, how long is he gonna live? How long's he got? What would you say, have a think.

And Probably, like all diligent vets, you'd go and look it up, and I might, I might forgive you for becoming very very confused. You'll find in studies like this with high risk mast cell tumours treated with surgery, blastine and prednisolone, survival of almost 4 years. And in studies like this one, survival over 5 years.

These are quite reasonable sample numbers. But be very careful here because sadly I don't think Dustin's got that long. Let's go back to the spectrum of aggression of our cell tumours.

When we categorise, then we kind of draw a line about here. I think it's about here, thereabouts. OK?

Where on one side of it, to the left of it we'd say low risk, to the right we say high risk. So for high risk, we tend to end up with this. In other words, there's still a spectrum of aggression within the high risk category.

OK. And sadly, tumours can be high risk if they are at intermediate patternic grade, but with a high mitotic count or high Chi 67 score. They can also be high risk if they're genuine high grade tumours.

And this shows in data like this surgery even been blasting and prayed for high risk mar cell tumours per se, had a good survival time. But for the patent grade 3 ones, it's pretty poor. 6 months And for those with distant metastasis to liver and spleen, again, it's pretty poor.

So for dogs like this, if they do well, I might say something like 6 to 11 months. But, sadly, the, the future isn't so rosy for these guys. My final case for tonight is Lucky.

Who is a 10 year old female neutered staffy again. It's got this horrible ugly mass protruding from a bottom. In fact, the owner noticed the dog was having issues defecating, that's why she took Lucky to the vets.

It's completely excised at referring practise, . But it rapidly recurred. And in fact, by the time the dog had post-op check, it looked like it was recurring.

This was given a patn high and pupil high grade designation. Referred to me and we staged the dog and we found metastasis in the sublumbar lymph nodes and in the liver and the spleen and the mediastinum. This was a very sorry state.

So, please consider what you would do, faced with a dog like Lucky. The tumor's been removed, it's high grade, it's metastatic, it's as nasty as Marcel tumours get. And it's recurred, so it looked like this when I first saw Lucky.

I've given you these options to consider. TKIs, Vinblastine red, revision surgery, then bin blastine pred, refer for radiation, or monitoring. Well, I went for TKIs.

OK, I, and I was very pleased to see within a month, the tumour had pretty much evaporated. And, and this is a little bit out of date now, but it's about 20 months, I suppose now, and she's still in remission. This is another dog I treated with mesitinib, and again, day 0 to day 28, the tumour has pretty much withered away to nothing.

And this dog actually came out of remission at about 22 months. And this is huggy here, OK? Hugging a 10 year old chihuahua, our cell tumour on the poor, which was high grade, metastatic, and resectable.

And this dog was on meitinib for 5 years. The tumour was completely controlled. And due to blood pressure, elevations, the dog had to be taken off meittinib.

But the tumour regrew. And the dog was put on mesittinib at a lower dose and the tumour went away again and eventually Huggy was put to sleep due to unrelated heart failure, some time later. So The reason why TKIs normally don't get such fantastic responses as in these three dogs is because there's a lot of redundancies.

Within cancer That is, we all know that you have to have a number of mutations to cause a cancer, and we can infer then that there must be a lot of aberrant molecular pathways within each cancer cell. If you're using a TKI you're just inhibiting one of these. So a lot of cases don't tend to respond because the other pathways compensate from the start.

And even if the, the tumour responds and you get shrinkage of the tumour, you're actually you're not killing cells, as we said, and you're applying a selection pressure. So you're gonna get it evolution of tumours that get round this particular path being abrogated at some point in the future. OK?

So, normally, you know, it's about fifty-fifty whether a dog will respond to a TKI. It's more likely to occur if you've got CI mutation positivity. But certainly not guaranteed.

If it does occur, it's usually finite. However, you do get some our cell tumour cases that do have a fantastic response to TKI's. This phenomenon is seen in people as well with things like melanomas, and we're talking about the vast minority of patients in the order of 7%, but it's great.

It's brilliant when it happens. And for cases like huggy and I hope, Lucky, the dog I showed you with the anal mart cell tumour, they can have a survival time that far surpasses the odds. So, why am I going TKI with this case and not with the other case?

I'll explain myself. In the setting of microscopic disease. Where there's nothing to measure.

That is where you've completely removed the tumour, but you think it's got a strong risk of spreading or it's been incompletely removed. I would use a finite course of cytotoxic chemotherapy. Viblastine and lemustine have been shown to be equivalently effective, but I'd go vimblastine all away because it has no cumulative effects.

It's much more predictable, and I would much prefer my own dog to have vimblastine than quite a lot of other drugs, for example, phenobarbitone. In this setting, remember that TKI's are not licenced and haven't really been tested. But the key thing is that we don't know whether they're working.

Now TKIS will work in about 50% of cases. If you assume they're working, you've got to keep the dog on it forever. So it's good to know whether they're working or not and if they're not working to be able to change.

And that's why I think it's important to have something you can measure. That is a gross tumour before using the TKI's. So an unresectable tumour with metastasis or strong risk of metastasis, I'd choose TKI as first line.

You can measure the response and for those who respond well, a minority will experience long-lasting tumour control. There's nothing wrong with using TKIs in the microscopic disease setting. I'm not going to have a go at you for that at all.

You've just got to bear in mind that it could strain the budget. If things are going nicely, you could be 14 months in, and you could have no money left to pay hundreds of pounds for drugs each month. There's nothing wrong with using thinblastine Pred in a gross disease setting because you can get shoot tumour shrinkage with these things as well.

But we've got a licenced alternative here. And we don't tend to see mutation addicted cases for Wasine or lousine. You're unlikely to get surprisingly good survival with these.

In difficult cases, you might find the tumour evolves drug resistance to what you're using almost before your eyes, and you might start with a TKI be going quite nicely, but 6 or 7 weeks in. You're gonna have to change because of drug resistance. And then perhaps you could choose Finblastine.

And then you might change to another drug like Lemustine or another TKI etc. So in the nastiest cases, you end up rotating around to find what works. So in summary then, most mast cell tumours will be cured with local therapy alone, around 80%.

Local therapy is indicated in all Mar cell tumours, but the high risk Marcel tumours will require medical therapy too. What are the high risksmart cell tumours? Well, start with looking at clinical and historical factors like anatomic location, growth rate, ulceration, breed, systemic signs, local lymph node metastasis, local recurrence.

And then use histopathological features like grade, proliferation in the sea, CI mutation status, hit protein localization if you want. If you get one of these all too common intermediate patent grade, low pupil grade mast cell tumours with a moderate mitotic count below the cutoff, where other prognostic factors seem very contradictory, I'd recommend requesting K 67 to try to clarify the situation. For treatment, Then intralesionaltiginol tigate stfonte is a very unique new local therapy for my cell tumours of all grades.

Remember the licence though, it needs to be non-metastatic, non-resectable, and below 8 cubic centimetres. Because it is specific to Marcel tumour vasculature, it can be a specific Mar cell tumour treatment that spares the surrounding skin, and I am very interested in using this drug in the surgically awkward areas. Where you have a high risk ma cell tumour, consider a course of chemotherapy, blastine Pred as the first line where you have microscopic disease only.

And I tend to consider TKI's more chemotherapy as first line treatment, we have gross disease that you can measure. If you want to see some other good webinars on Marcel tumours, there's my one from last September. I'm biassed.

Funded by Verba and available free. And to learn more about Selfonte, of course, you've got Pam Jones did a sister webinar to mine, specifically going through use of steel Fonte. And if you want to use Steel Fonter, I'd really encourage you to have a look at this.

There's lots of practical tips here. And you can tell that Pam has been treating sick animals for the vast majority of her career. She gives lots and lots of tips and lots of useful advice.

I've written an article or two articles now, and that are going to be in Companion magazine in the next few months or so. Look out, look out for those. They'll be going through in detail how I'd navigate prognostic tests or treatments for our cell tumours.

And if you're interested in cytology and veterinary oncology, I'd encourage you to look at these Facebook groups here, veterinary cytology and the ESON site. Like to acknowledge my colleagues who tolerate working with me every day. And I'd like to say massive thanks to the guys at Webinar Vett for asking me to speak again and to you all for coming along to listen tonight.

If you've got any questions, please let me know. Thank you ever so much. Owen, thank you so much.

And as Anthony likes to say, if we were in an auditorium now, there would be a rounding raising level of applause. You are not biassed, your webinars are absolutely fantastic. They are not only informative.

But they are incredibly practical. And, it just allows us mere mortals in, in private practise to just feel like we can actually cope with these sometimes frustrating conditions. So, thank you so much for your time and your effort that you've put in.

No, pleasure, pleasure. And folks, I would strongly, strongly recommend if you missed Owen's last, webinar, on the Marcels that you go and have a look at it. Owen is, rightfully not being modest about it.

In fact, he's underselling it dramatically. And, Pam. One on the Dell Fonte as well was, was really a worthwhile, view.

So if you miss those, go and have a look at them. And, I'm sure in a couple of days, you will want to go back and have a look at this one again once we get it up on the website, as it will be, very shortly. Owen, we don't have any questions coming through, but we do have a lot of, of thanks to you.

And, people seem to have enjoyed it just as much as I do. Which I'm not surprised about. So once again, thank you for your time.

It's a pleasure. Thanks. Thanks for attending tonight.

As always, we appreciate it and to my controller Dawn in the background, thank you for making everything happen seamlessly and from myself, Bruce Stevenson, it's good night.