The last session is are really some cases that I think Doug and I have put together and I'm going to do the 1st 25 minutes. I've actually put quite a few together and it's really how far we get in 25 minutes. So really they're tales from an oncologist's casebook, which is also the title of my memoirs.

The, Just to point out, being an oncologist, I think you have to understand internal medicine, you have to understand surgery, you have to understand surgeons as well, and you have to understand radiation. So essentially you're the sort of jack of all trades, but also . The owners expect you to be the master of all trades as well.

So it can be quite challenging. So these cases that that I've I've put together are really a selection to highlight how sort of internal medicine and surgery and radiation come together and And they are genuine cases, cases that have been sent to us in the university, and they just highlight a few things where I think it's important just to have an understanding. So I wanted to start off with this rather sad looking dog.

This is Bobby. He A, so I'm losing control here. This is, Bobby's an eight year old, Bassett, and, he was a male dog.

He was castrated at one year of age. And he'd been in the owner's possession for all of that time. So it was bought as a puppy, regular vaccinations and checkups, and no major health issues at all until he presented to us.

So his his recent history though, this was a classical. The afternoon referral into the university. He'd been quite bright and alert, but he'd been polyuric and polydipsic for the past two weeks, quite excessively, according to the owners, continually drinking, and his appetite was reducing, although he was still eating when when we saw him in the afternoon, and he was referred.

With a biochemical diagnosis from the referring practitioner of hypercalcemia, that was a raised total calcium, of course, not not an ionised calcium. And on clinical examination, he was in very good body condition and, you know, hadn't obviously had a reduced appetite for very long. He was bright, alert, and responsive and essentially when we did the clinical examination there were no clinical abnormalities at all, and that included auscultation of his chest and abdominal palpation.

There was nothing around the anus at all, nothing around the perineum, rectal examination was normal. Oral examination was normal, and his temperature was was normal. And so couldn't find anything at all.

His lymph nodes were all of a normal size and for all intents and purposes, and he seemed to be in very good health despite his hypercalcemia. So in terms of our differential diagnosis list, if you like, we have a lab error, obviously could be a problem here, especially considering his his good normal physical examination, but don't forget he was also polyuric and polydipsic. And malignancy and tumours certainly high on the list of differentials for hypercalcemia.

Hence he was sent to an oncologist and of course lymphoma and apocrine gland adenocarcinoma very, very high on the differential diagnosis list there. Hypoadrenal corticism, about 28 to 45% of dogs have a high total calcium, sometimes with a normal ionised calcium actually in Addison's disease, and the hypercalcemia is thought to be due to enhanced absorption of calcium in the GI tract, sometimes hemo concentration or decreased glomerul filtration rates from volume contraction and perhaps increased complexity. And protein binding of of of calcium in in these cases.

Primary renal failure, actually, it's been my experience that very few primary renal failure cases actually have hypercalcemia, and it's usually the other way around. Hypercalcemic dogs tend to have compromised renal function, although in the litre literature, it does suggest that 10 to 20% of cases. Especially dogs with inherited renal disease, can have a raised calcium level.

However, in these dogs, often the ionised calcium is, is, is normal or even decreased. And hypervitaminosis D, it's not a terribly common diagnosis, although, essentially some of the neurodenticides contain choliccalciferol and are quite widely available, and they can actually produce marked hypercalcemia in dogs quite rapidly when they've ingested this. I would say as well, some, some lymphomas can can produce vitamin D.

Hyperthyroidism is another cause of though, it's my experience, it's quite rare to see that in hyperthyroidism, and of course, some bone lesions can cause hypercalcemia as well. Granulomatous disease, again, in things like blastomyces, which is certainly not common in in this side of the Atlantic, but widespread granulomatous disease can lead to hypercalcemia. Just to remind you about calcium homeostasis, and that's essentially what it is, it's to maintain the calcium within a very narrow limits.

It's through the interplay of parathyroid hormone calcitonin, calcitriol and again parathyroid hormone. Maintaining calcium within the normal limits, allowing excretion from the kidney and controlling absorption from the gut and and maintaining bone levels or increasing the the ionised calcium in the serum. And again just to remind you, as I said, this dog was referred with a raised total calcium, and that total calcium includes the 10% diffusible but non-ionized form, the 40% protein bound form, and only 50% of that is biologically active, which we tend to refer to as the ionised calcium.

So hypercalcemia, often a consequence of of deregulation of homeostatic mechanisms. The most frequent cause in the dog are are malignancy, and second to that is hypoadrenal corticism. In the cat, it's often malignancy, renal renal failure, and we also recognise idiopathic hypercalcemia in cats, which just means we don't know what what has caused it.

Nearly half the total serum calcium is bound to albumin, so we often want to measure the ionised calcium, and biologically active ionised calcium can also be increased by acidosis and certainly should be assessed using heparinized anaerobic samples. So let's think about this dog in a little bit more detail. We've done a clinical examination.

We've found it to essentially be normal. When we did haematology, he had a mild non-regenerative anaemia. He had a hematocrit of 28, which is quite significant then that's a pack cell volume of 0.28 litres per litre and was mildly azoic.

His calcium levels, we, we obviously wanted to recheck the total calcium to make sure that that wasn't a lab error. And we also measured his ionised calcium as well, and on both of these, his total calcium was raised at 3.7 millimoles and his ionised calcium was also raised at 1.9 millimoles.

So he definitely was hypercalcemia. So like every good oncologist, we moved to radiography. His radiography was absolutely normal of the thorax.

That was 3 views, right, left lateral, and the dorsoventral and we couldn't see any any bony lesions either. We did ultrasonography of the abdomen and couldn't find anything there either. We also palpated his neck, couldn't find anything there.

And we then sent blood for both parathyroid hormone and parathyroid hormone related peptide. And just to explain this, so PGH is the parathyroid hormone. PTHRP is parathyroid hormone related peptide, and I'll just explain that again in a moment.

Essentially this should be less than 1.8 moles in an adult dog. Parathyroid hormone is often raised in primary tumours of the parathyroid, and that's about 83 plus or minus 38 grammes per mL.

The parathyroid hormone is low and a raised parathyroid hormone related peptide in some tumours that are associated with parathyroid hormone related peptide, hypercalcemia. And what Bobby had was a low normal parathyroid hormone at 18 picograms per mL. And his parathyroid hormone was raised at 45 moles.

So we considered this possibly associated with a tumour somewhere. In terms of hypercalcemia of malignancy, where we do think there's a tumour, most dogs, 2/3 of dogs that present with a biochemical diagnosis of hypercalcemia are subsequently diagnosed with cancer in about 1/3 of cats, and the most common one we certainly see is lymphoma, but you can see it in things like anal sac adenocarcinoma and multiple myeloma. Bobby, then, there was no evidence of a tumour at all on all of our imaging.

There was nothing on physical examination. PTHRP is actually not an abnormal protein. It is present.

It's involved in cell regulation in the adult, though it's very low or or certainly you can't really find it in in the in the serum. But PTHRP when it's raised, is often consistent with malignancy and certainly his levels in this dog were consistent with malignancy, despite our inability to find a tumour. So at this point, again, like every good oncologist, we went for a bone marrow biopsy, and essentially what we found was this picture.

And what Bobby had, of course, was a leukemic pro lymphocytic leukaemia. Now the importance of the hypercalcemia here was that this dog had leukaemia, but it was a leukemic, and that means that there was no real evidence hematologically in his in his blood smear of neoplastic cells, although he was starting to become anaemic, all of the tumour was located in the in the bone marrow. And interestingly, the hypercalcemia, of course, was the first indication that there was something wrong with this dog, which was really very critical for this patient because it means we could get treatment underway fairly quickly.

So hypercalcium and malignancy, as we said, it's it's really very important in many tumours. The effects, of course, are that you get renal and pre-renal azotemia, degeneration of the urinary epithelia, polyuria, polydipsia as a consequence, vomiting, dehydration, of course, it can have a major effect on the nervous system as well, and you can get anything from tremors through to coma with these. So the clinical features are often gastrointestinal, neuromuscular, CNS renal, and cardiovascular, but it really depends often on the magnitude and the underlying cause.

So in terms of managing this patient in terms of his disease, first of all, we wanted to get the calcium under control, and this is usually very simple. You want to promote the external loss of calcium and increase renal excretion and inhibit bone resorption, and you know, it's based on fluid therapy to increase the GFR, increase calciuris, and decrease calcium reabsorption. And sorry, that's gone in reverse order for some, and these are the kind of things that you can, I'm not going to go through it in any great detail.

It's what you can do in mild, moderate, and severe hypercalcemia. The key thing about Bobby is that he was actually quite well. He went on to fluid therapy at 2 to 3 times maintenance.

I'll be honest with you, most of these dogs, it's actually very difficult until you start treating the underlying disease to actually bring the calcium down significantly, but The one important thing to do is if you get these dogs on the fluids, the one thing, of course, that will bring down calcium quite significantly or corticosteroids, but please avoid corticosteroids till you know what you're dealing with, because certainly if you've got a lymphoma that's not diagnosed, you will mask the diagnosis. Things that you might see in the textbook are mithromycin and gallium nitrate. Please avoid these.

They're really bad to use, handle and treat patients with, and stick to things which are appropriate. In this dog, we actually just use fluid therapy and started. In the underlying cause, but in ones where you've got refractory cases that where you haven't made a diagnosis yet, you can use short acting calcitonin or bisphosphonates to bring down the calcium level.

Remember, bisphosphonates, things like zolidronate, permidronate, Zidronates a more potent drug than permidronate, but much more expensive. So we often use permidronate by slow IV infusion in refractory ducts. We treated this dog with chlorambusil and prednisolone.

His white cell count normalised. He actually went on for 3 years, and the first sign that the disease was coming back was actually the hypercalcemia return. So again, using calcium almost as a biomarker in this disease.

That brings my hypercalcemia case too, yeah. David, shall we see if Doug wants to comment on that one? Yes, absolutely.

I guess my only thing that I found quite interesting about this case is the fact that your PTHRP was elevated. And that's, I guess, not something that I see as much with the leukemias as I do with the, with the anal sy tumours. Yeah, absolutely, and, and although it can be, we've seen a couple of leukemias like that.

It wasn't, it wasn't huge though, Doug, you know, it wasn't hugely elevated. Yeah, but we couldn't couldn't couldn't find anything anywhere else in this dog, which was quite, quite amazing, which is always a pain on a Friday afternoon because you expected, we expect to find a lymphoma or an anal sac tumour. Yeah, good case.

The next 3 cases I'm going to deal with altogether and I'm conscious of time. I was obviously being a bit more ambitious when I wrote these, so, but, but these 3 cases are reasonably linked. I wanted to make a point with with some of these.

This dog is Zeus is a 10-year-old male boxer, and he presented to us with weight loss and lethargy. His haematology had a non-regenerative anaemia, pack cell volume 27 litres per litre. Is diff white cell count and, and, .

Platelet count was normal. He was mildly asotemic. The key thing on his biochemistry that is albumin was 14 grammes per litre, and that just make note of the units in the states that's often grammes per deciliter.

So our range there would be 26 to 35, so he was hypoalbuinemic, and his globulin level was 88 grammes per deciliter. Again, our range would be 18 to 37. So it's, so its total protein was, 102, that should be grammes per litre, by the way, not deciliter.

A consideration in these cases, again, is that the major biochemical finding is that he had a gammopathy. And this is a range of diagnostic workup things that we might do in the face of finding a gammopathy in dogs, including CBC chemistry, urine analysis, chest radiographs, bone marrow skeletal radiographs, coagulation profile. The key thing for us is to know in terms of this gammopathy, if you like this high globulin level, whether we're dealing with a monoclonal gammopathy or a polyclonal gammopathy, and where we find a gammopathy like this, we should always perform a serum protein electrophoresis.

Polyclonal gammopathies tend to be associated with chronic infections, and monoclonal gammopathies tend to be associated with tumours, although you can see it sometimes in olichiosis or indeed in cats in feline infectious peritonitis. So just to remind you about plasma proteins, this is a serum protein electrophoresis from a normal dog. What you find is often you'll see .

A rise in oops sorry, a rise in albumen and then you get the alpha and beta fraction and then the gamma globulins, and that's the sort of peak that we're looking at there in the gamma fraction whether that's a narrow spike indicating a monoclonal gammopathy or a broad peak indicating a polyclonal gammopathy. And of course just to remind you, the globulins we're talking about the gamma globulins and in particular things like IGG, which is on the left of your screen and IGM, which often gives you a very big pentameric structure where you get IGM gummopathies often these dogs have quite marked hyperviscosit syndrome. So again, looking at these cases, we might suspect a tumour on the tumour side for monoclonal gammopathies, we might think of something like multiple myeloma or lymphoma in multiple myeloma, you can often see punched out lesions in the radiographs in in the.

In the flat bones, this is in the spinous processes here. Sometimes you'll see that in the sternum in the ribs, and here we've got a fracture here and what you tend to see is a marked monoclonal spike in these in these patients. This dog was quite interesting.

He had, ecchymotic haemorrhages on his, his retina, and his bone marrow biopsy was highly indicative of, a plasma cell, tumour. So we diagnosed in this dog based upon his bone marrow aspirate based upon his monoclonal gammopathy that he had multiple myeloma and he was treated with malalan and prednisone. I really enjoy treating these cases.

The response rate is very, very good. He responded quite well. We monitor these quite closely by looking at their immunoglobulin levels, and usually you find that you treat them for a little while and then suddenly the mono.

The gammopathy comes down to near normal levels, poor prognostic factors with these dogs as if they're hypercalcemic or if they get bone lysis or they've got significant Ben Jones protein urea. Eventually they do relapse, but we've had some of these dogs going on for a number of years before, before relapse. Some of these dogs have done very well.

. This is linked to the next case because I wanted to just to compare it with this dog, and this is Toby was a seven year old entire German shepherd. And he actually was presented or referred to soft tissue surgery service for an inability to pass urine. And this was really a very, very unusual case from the point of view is that the surgeons actually took a blood sample, and that's that, that can be quite rare in the hospital sometimes, but they took a blood sample and found that they had a mild neutrophilia with a left shift, a mild nonregenerative anaemia.

He was azotemic, but again, his albumin was 16 grammes per litre and his globulin was 102, so he had total protein of 117, so he had a massive globulin level and it was proteinuric. And so what we have here, this was serum protein electrophoresis results. He was immediately sent to us in oncology as a multiple myeloma from the surgeons.

They said, please come and collect the multiple myeloma from ward 2. So we went along. Had a look at the dog.

In actual fact, when they passed the catheter, it was able to pass urine again, don't know what that was or what the origins of that was, but what we did find here, of course, is that the dog had actually a polyclonal spike, didn't have a monoclonal gammopathy at all. So what we did here, we did like every good oncologist, and we went back, of course, and we took a history which the surgeons hadn't took, and when we took a history from the client, we found, of course, the dog had come in from Spain 6 months previously. And I had no signs of ill health and we couldn't find anything anywhere else.

We did a bone marrow biopsy and of course what we found was this dog had had leishmaniasis. So this was an an a polyclonal gamopathy this time with an infectious cause. And I just want to link this with this case here.

This was a 10 year old castrated male dog cross terrier. He was referred again with a non-regenerative anaemia. His actual anaemia was quite marked.

It was 0.14 litres per litre. He'd had profuse watery diarrhoea for two weeks.

He was actually really bright in himself though, and that was a surprise to me how bright he was when I looked at his blood results. His ama group was 14%, as I said, or 0.14 litres per litre.

So it was quite anaemic. So it's obviously been anaemic for some time. And his biochemistry, his albumin was only 6, which was, if I remember the textbooks correctly is inconsistent with life.

And it didn't seem to be edematous, but his total protein was 108, and his globulin was 102. So very, very dramatic biochemical changes and he had a marked protein urea. And again, what we have here on his serum protein electrophoresis, he has a marked monoclonal spike, and of course, very little albumin.

Albumin, well, well, certainly in these diseases often you find immune complex disease in the kidney and, and glomerulone nephropathy, so you can get protein leakage, but the main reason this dog, had, his, condition was, was, was, this is his, GI tract. This is a postmortem finding. This dog had, a B cell, immunoglobulin secreting B cell lymphoma of the GI tract.

And the point I want to make in, in, in these all of these three cases is that not every gammopathy is, is multiple myeloma. Certainly not every monoclonal gammopathy is cancer. And please look at the clinical features as well, because in this dog, it was actually straightforward to diagnose this very clearly early on.

He'd had profuse watery diarrhoea for two weeks. It's non-regenerative anaemia, and this was adding up more to a lymphoma case rather than a multiple myeloma. Now, I'm conscious of time, I've got more cases, but I think I probably should, one, let Doug come in at this point and make any comments on the previous cases, and perhaps pass over so Doug can do his cases as well.

Thanks David, passing over to Doug. What, what are your thoughts on those, Doug? Those are great.

So we, we don't see here in the states. But we do have some other infectious diseases that can be associated with monoclonal gammopathy, especially some of the tick-borne diseases such as Erlichia and Rocky Mountain spotted fever. And I agree with you 100% that I love to treat multiple myeloma, although I rarely get the chance these days because it's treated so effectively in practise.

But here in the states, there is one thing that's really changed for the worst, and that's that the cost of, of melphalan has just shot up astronomically. So it's, it's about $15 a day to treat a a 60 pound dog, you know, a 30 kg dog at this point, and that's really become a problem for many of our clients that's made the treatment of multiple myeloma not quite as rewarding as it used to be. Yeah, yeah, because these dogs do go on for a significant length of time, you know, you can treat them for some time.

Yeah. And of course, I suppose the interesting thing about the leishmaniasis is that that also opens a whole can of worms because you'll get dogs who are obviously leishmania positive. I know you saw parasites there, but, may not be significant because I think about 60% of dogs in endemic areas are, aren't they?

Yeah, well, I, I have to say that I did see, I mean, we've seen an increase in in some of these cases in the UK. The, obviously the, the pet passport scheme, you know, you see these dogs, dog to dog transmission has been recorded now in the UK, which is, which is quite significant. But I did see one dog that had some of these present like a multicentric lymphoma.

And the practitioner had been treating it for lymphoma. So it was, and it just wasn't going. It came into us as a dog that was failing to go into remission.

And of course, Leishmania loves corticosteroids and and. And, and, you know, the parasites were hoaching on this dog. But I think it's an important distinction because often these dogs do present like a multicentric lymphoma, that big lymph nodes.

And it'd be very easy just to, just, just to treat them without investigating further, but it is a concern in the UK as we get much, much greater dogs are able to move freely now across the border. I actually did a webinar on it as an unusual case study in dermatology, so those of you who are on the platinum can have a little look at that as well just as a. It's a differential not to forget about, and I think this is, as you say, David, where history is so important, you know, travel history, I think is, is becoming more and more this this particular dog I saw, you know, the people had gone over to Greece, found a stray dog and brought it back from Greece and we've got so many stray dogs in the UK it doesn't seem to make a lot of sense.

Well, that's what people do. It's quite some frightening statistics now about the number of stray dogs, and it is actually this . picking up stray dogs in foreign countries and bringing them back is becoming more, I think the UK is, is gonna face a bit of an issue in that area.

And of course zoonotic as well as can be spread. Absolutely, yeah, it brings up some, yeah, difficult questions about how you manage those cases is, you know, what you do ethically. Doug, it's a disease that you probably don't want to have in Colorado, really.

No, I'm, I'm pretty glad that we don't have it actually. I think it is in some parts of America, but it would be right down in the south, presumably because I think there's some in Brazil and places like that isn't so presumably it's pushed up into southern America. Yeah, just a very, very deep south of the country.

Yeah, yeah. Great, Doug, we'll swap over to you and . Let's get these other cases started.

We can always look at time, you know, and see if people want to stay a little bit longer if there's other stuff still to still to look at. Great. Well, I, I think I've got 3 cases here and I may be very much in the same boat as David, in that.

I, I, I may not get through all of them, but, I certainly will, do our best, and if we need to stop after just 1 or 2, that's completely fine. So, Actually, the first case that I'm gonna talk dovetails a little bit with with something that David talked about, which I think is kind of nice. So, this is Newern Labrador retriever, who was actually presenting to us for a mass that the owner actually noticed under the tail in the past week.

And this sort of has coincided with a little bit of strain to defecate. But otherwise, according to the owner, really appetite, attitude, and activity level all seem to be normal. The, the dog may have been drinking a tiny bit more water than than normal, but has not been asking to go out more frequently, has not been having any urinary accidents in the house.

So it's really on physical exam, the, the abnormal findings were limited to the presence of this of this perianal mass, and the exam was otherwise unremarkable. So some of the things that we always want to consider. In a dog with a history of a perianal mass.

Of course, abnormalities, non-oncologic abnormalities with the anal sac are always on our list. So anal sacculitis, impacted anal sacs, anal sac abscesses. And then of course, there are 3 kinds of tumour that we see with relative frequency in the perianal region, and these include the perianal gland or sebaceous adenomas, the perianal gland carcinomas, and the apocrine gland carcinomas of the anal sac.

And a good rule of thumb that I always try and help my own or help my students remember is this one, the perianal gland or sebaceous adenoma, is the one that we're most likely to see in the intact males. Or entire nails as, as you folks say across the pond. And these others are, are somewhat agnostic of of what the, what the signalment of the patient is.

But, certainly, there are exceptions to that rule. We, we certainly do see intact male dogs who develop anal sac tumours, and we certainly do see, occasional castrated males or or female dogs actually who do get perianal adenomas. But it's the big parental gland adenoma in the intact male dogs that I think is a good rule of thumb for.

Students to remember. The other thing that I think is worth hammering home is that there are other kinds of cancer that we can see in the perianal region. We certainly can see mast cell tumours, for example, in that area, squamous cell carcinoma, especially in the skin of the perineum, soft tissue sarcomas.

And interestingly, there are now probably half a dozen. Cases or so that, that we've seen here at Colorado State of melanoma of the anal sac itself. So, you know, not a cutaneous melanoma of the haired skin, not a mucosal melanoma, but a melanoma actually in the anal sac of these patients.

So that's another kind of oddball differential diagnosis that you'd want to have on your list. So obviously, the really important things on a physical exam that we want to take a look at are the tumour itself. So how fixed is it, how large is it?

Does it seem to be crossing midline? Does it seem to be infiltrating into the pelvic canal? And again, depending on the size of the patient, sometimes we may be able to feel subliminbar lymph node enlargement if the lymph node is very huge and if the dog is not too big.

Our fingers are not nearly as sensitive as some of the other imaging tests that we're capable of doing to determine whether or not there's a medial iliac or sub lumbar lymph node involvement as well. And again, even though this seems like kind of a thing that may be, may be challenging, it's actually usually quite simple to do fine needle aspirates on these, on these perianal or anal sac masses, and that's usually going to be our first step. And trying to determine what's going on.

So, the very first time that we actually did our fineasperate, this is the, the story that we got. So we got a an appearance that really looked far more significant for piagranulomatous inflammation. Than one that was consistent with tumour.

But based on the size of this and, and the adherence of it, I really had a hard time believing that this was actually an inflammatory condition. These anal sacs were not expressible. We didn't get any pus out of them.

And again, this was pretty large and adherent. And for that reason, I really said, yeah, I'm not so sure I'm gonna believe this. I elected to reaspirate immediately, and the second time we got an appearance that looked much more like this.

And this is a pretty common appearance for actually most of the tumours that we see in the perineal regions. So this is an appearance that could be consistent with a perianal gland tumour or an anal sac tumour. So they don't look particularly aggressive cytologically.

The cells aren't very huge. There's not an enormous amount of variation in their size and shape. And again, this isn't a that's fairly consistent with a perianal gland tumour of some sort.

One of the, the little tips and tricks again, that I try to reinforce with the students is that sometimes it can be very difficult for the clinical pathologists to actually make a call of malignancy by looking at these cells. So if they don't know, for example, where the tumour came from, they may be likely to call this a Benign process, because again, the cells just don't look that aggressive cytologically. So anytime you might get a pathology report back after you submit, a fine needle as sample like this, even if it says, hey, this looks like a benign tumour, really need to take that with a grain of salt based on the signalment and the clinical appearance of the patient because that can be misleading.

So, on our baseline blood tests, our CBC was really completely unremarkable. And on a chemistry profile, this dog actually was modestly hypercalcemic. Our units are different, but this dog had a total calcium of about 14 milligrammes per deciliter, and, and, an ionised calcium of about 1.65 millimoles per litre.

And again, both total ionised calcium was a little bit elevated in this patient. And again, is that surprising? No, as David mentioned earlier, we certainly do see about 40% of dogs with anal sac tumours may have hypercalcemia.

So that's definitely one of the things that's quite high on our differential list when we have a dog that presents with a biochemical abnormality associated with hypercalcemia. So, the next thing we did, because we're good oncologists, is we started doing some additional staging on this patient. And really quite, quite unexpectedly, we on abdominal radiographs, we actually found massive sublumbar lymphadenopathy.

So this is, would be a fairly easy determination to make just on a plain flat film of the abdomen. But one important take home message is that these kinds of appearances are really the exception rather than the rule. So you can have quite sizable sublumbar lymphadenopathy that's not gonna be clinically apparent on radiographs.

So for that reason, ultrasound is really a much more sensitive modality for evaluating that sublumbar region. Unless we have something that's quite, quite obvious, we usually will default to ultrasound without even obtaining radiographs of the abdomen, just because of its really significantly enhanced sensitivity. I'm gonna back up just a second and, and make one other point here is that sometimes we can really be quite surprised by how large the sublumbar lymph nodes can be when the primary tumour can actually be not that, not that big at all.

I can remember one or two cases where I've actually seen sublumbar lymph nodes that look like this, and the primary anal sac tumour has been pea size, literally that small. So it seems hard to, to make a good sense of, of how that can occur from a biological perspective, but it is certainly something that we see occasionally with anal sac tumours. I see it occasionally with tonsil or squamous cell carcinoma too, where the primary tumour can be very, very small and the metastatic lymph node can be quite large.

So we always take thoracic radiographs on these patients because again, that's what we do as oncologists in order to be complete. But actually, in our practise, the likelihood of finding abnormalities related to tumour on a chest film in a, in a previously untreated anal sac tumour dog is actually quite small. In our hands, it's in the neighbourhood of 1 to 2%.

So it's actually in an intern project that was performed by one of our interns a couple of years ago. I think it's almost as likely or more likely that you could find another unrelated abnormality in your chest X-rays that could potentially change how you wanted to move forward. So a separate unrelated tumour, occult cardiac disease or something else.

So it's a very worthwhile insurance policy, but certainly a low yield diagnostic test. And if you have an owner where they really need to prioritise the testing that they do, for financial reasons, for example, I think the chest film would probably be at the bottom of the list of, of things that I, that I do if I have to pick and choose. Very recently, actually, two, well-known UK oncologists, Jerry Poulton and Malcolm Brearley, actually have published a really nice, staging system for dogs with anal sac tumours that actually does appear to carry quite a bit of prognostic significance.

And you can see actually the stages are listed on the far left here. The first two stages, are different, are different sizes of primary tumours without any evidence of lymph node involvement. Stage 3 involves lymph node involvement of different sizes.

And then stage 4 tumours are tumours that have gone beyond the regional lymph node. And as you can see, there's a a quite dramatic difference in long-term outcome between dogs that have these early stage tumours and dogs that have these later stage tumours. But I think an important take home.

Is that with surgery, even dogs that do have fairly sizable regional lymphadenopathy can have a reasonably good outcome with surgery. So we don't write these dogs off simply because they do have disease, for example, in the regional lymph node like our patient here does, we just do tend to potentially treat them more aggressively systemically. So, anal sacculectomy is a pretty routine procedure and obviously it does form the mainstay for the treatment of this disease.

Either a simple anal sacculectomy if the disease is still regulated to the anal sac or a larger perianal resection may be necessary. There certainly are some complications that are well described from this procedure, and these include infection. This is obviously a dirty area and dehiscant.

And one of the ones that's talked about actually an enormous amount in the literature is this thing about incontinence. And back sort of in my previous lives, we used to, just, just really put the fear of God into owners about incontinence and oh it's gonna be awful and oh we can't do surgery on this. And one of the older sort of myths was that if it crossed midline.

Then the risk of risk of incontinence was much, much, much more high. And now I've, I've been doing this for about 15 years, and again, I've been working here at Colorado State University with a, a cadre of incredibly accomplished surgical oncologists, and really we just don't see incontinence as a major problem from these patients. At the end of my little discussion, I'm very keen to know if David has a different opinion about this, but we just do not see it.

And my, my colleague and, and mentor, Doctor Steve Withrow, who's pretty much the the founder of the founding father of surgical oncology, says, yeah, you know, even in these really, really huge tumours that cross midline, once in a while, you can see incontinence, but it's not complete. It's not complete and utter faecal incontinence. What we're left with is what, what Steve calls doorbell poopers.

So, you know, they may get very, very excited and occasionally have some mild incontinence, but most of the time they're just fine. So it's not nearly as much of a concern in my practise as I thought it was when I first got into the business. What about lymph node extirpation?

So again, this is something where if we do see disease in the node, but not beyond, we will not hesitate to go in after these nodes. And if you look across the board again in our hands, in the hands of our surgeons, I should say, I can't even do a cat spa, Our, our surgeons will say about 70% of the time they're able to actually get those lymph nodes out pretty easily. And about 30% of the time, either they're so adherent.

To, you know, kind of the ventral lumbar structures that they can't be removed safely, or they just kind of fall apart when they're touched. And again, also can't be removed safely. And again, talking to our, our surgical oncologist, they really don't feel like pre-surgical imaging, even advanced imaging like CT and MR really will give them a good sense about whether an individual sublumbar node is resectable or not.

It's really something that they won't know until they get in there. So surgery definitely plays a mainstay of the role here and that's certainly what we performed in this patient. Radiation therapy is also something that can be utilised for the treatment of this disease.

The outcome associated with radiation therapy actually can be quite favourable. So the best outcome that's ever been reported in dogs with, with anal sac tumours. Actually employs a combination of surgery, chemotherapy, and radiation therapy.

But radiation therapy to the perineal region is nasty business. It's really uncomfortable for the dog. There's really no way in the postoperative setting for our new fancy targeting technology that I mentioned to address this.

You really still have to shine down radiation onto the skin of these patients, and it is very unpleasant. There are some late-term complications, for example, rectal and colonic strictures that can be quite problematic and it certainly is very costly as well. In this particular case, radiation therapy was declined by our owner.

So what about medical therapy? So, there's comparatively little known really about the true efficacy of medical therapy for for anal sac tumours. And different oncologists will use different agents, kind of the list that's up here is is the list of where there's at least some hint of activity in the literature.

In our practise, we tend to Usually reach for carboplatin first. And I think one of the reasons is, again, it's, it's well tolerated and it's relatively inexpensive. But the other is, this is one of the few tumours in the literature where objective tumour regressions have been observed.

So in other words, if you give a dog with a big anal sac, tumour carboplatin, some of those dogs will actually have meaningful tumour shrinkage. Now, that may very be the case for the other agents, but to my knowledge, there isn't anything reported in the peer review literature documenting that. So for us, carboplatin is really what we reach for for these patients, and that was what the owner elected to do 5 cycles of carboplatin following surgery.

And we typically start right around the time that the sutures are coming out at that sort of 2-week recheck. So, following our 3 doses or 4 doses or 5 doses of carboplatin. This dog went on to receive quarterly rechecks of the local site, the regional nodes which are assessed by ultrasound, and then usually every other recheck will resuit chest X-rays as well.

Again, a low yield diagnostic test, but not zero. And in this particular patient, the, the local site remained quiet for a very long period of time, but relapse was noticed. In the sublumbar lymph nodes, after about 18 months of treatment, or about 18 months after treatment was, was completed.

So, what do we do with this patient? Well, actually, one of the things that's been pretty well documented is that actually serial lymphadenectomy can actually be quite successful in some of these patients and can result in fairly long survival times. So, there was a, a, a small case series reported in vet surge about 6 or 7 years ago that actually looked at, I believe, 5 or 6 dogs that went on to receive serial lymphadenectomy after initial, Detection of, of lymph node metastasis.

And one of the dogs in this case series, I think, had 5 lymph node surgeries over the course of 3 years and actually did quite remarkably well. And then the question becomes, well, if you're able to get this dog back down to microscopic disease, is there a role for employing some other kind of alternate chemotherapy at that point to try and delay or prevent metastasis? And I would argue that there is.

There's also some reports of palliative radiation therapy, so weekly, very conservative radiation therapy being helpful for these patients. But in our patient, what we actually chose to do was go back in, re-resect those lymph nodes, and then switch to doxorubicin. And in this particular patient, We actually had relapse in the next lymph node up the chain about 6 months later.

And at that point, the owner did decline, further surgical intervention. So what did we do at that point? At that point, we actually switched this dog to palladia, as I mentioned previously.

And again, there's some information that suggests that palladia can be useful in some dogs with anal sac tumours. I showed you this slide before, so I'll just reiterate it, paying special attention now to the anal sac tumour dogs. So, in 32 dogs with anal sac tumours, about a quarter of them had meaningful tumour shrinkage.

And again, in oncologic terms, that usually means that the tumour reduced in volume by at least 50% or reduced in maximum diameter by at least 30%. And the median progression free interval in these patients was about 25 weeks in the patients that experienced partial response or stable disease. So in this particular dog, again, we went from a median maximal diameter of about 11 centimetres prior to palladia, and after one month of Palaia therapy, this tumour was reduced to about 7 centimetres.

So, you know, a nice partial response, certainly not a complete response, not something that we were expecting, and a dog that was otherwise clinically asymptomatic, we would have been quite happy even with stable disease in this patient. And this patient went on to have stable disease for an additional 6 months or so. And at the end of that period of time, actually it was local progression that was the problem with this patient.

So one of the interesting facts about this patient is at the time of relapse, this dog's hypercalcemia did actually not recur. And that's really brings up a kind of an interesting point about what's called clonal heterogeneity. So not every tumour cell in a, in a tumour is gonna be exactly the same and for whatever reasons, The tumour cells that chose to make up this relapse were not capable of causing hypercalcemia.

And this is actually something that we see occasionally in either direction. So sometimes we'll see normal calcimic patients that become hypercalcemic at relapse and hypercalcemic patients that are normal calcimic at relapse. Statistically, dogs that present with hypercalcemia do tend to be on the short side of the average marks that are described in the, in the Poulton paper.

And I think the reason for that probably has to do with not necessarily that it implies a different biology of the tumour, but those dogs are more likely to have problems with their calcium, leading to poor quality of life, etc. Than they are with actually the occupation of space by the tumour masses. So that management of the hypercalcemia may become a clinical problem first, and my guess is that that's probably why they tend to have shorter median survival times.

And I think in the interest of time, I'll probably stop at this point and again entertain any additional questions and any comments that David would like to make. No, I think, . That's great.

I'll pass over to David. Yeah, very, very interesting case, Doug. The, only just a couple of comments.

We've gone in terms of radiation treatments. We we see a lot of these patients and, and I agree with you on the surgery, anal incontinence is incredibly rare in these dogs, even with really big tumours. The only thing that we've done slightly different with radiation now, we go for quite small fractions, but more, more of them.

So we've and we've reduced the sort of side effects in terms of rectal structures or colonic structures. And, again, like yourselves, we go for for carboplatin, but it's an expensive protocol, but I think in terms of risk benefit these dogs do incredibly well with that, that, the combined the radiation followed by chemotherapy. So that was actually the question I was gonna ask you, David.

So when you do radiation and chemo, do you actually wait until the radiation is complete to Yeah, we do. So we go through radiation and then they start carboplatinum. And that I think it was when we were combining it we were getting so many side effects and actually the dogs do, the dogs do very well so we complete the radiation, they go on to to carboplatin after that.

Excellent. That's interesting the way that you were able to sort of re-rescue with the palladia as well and get the, the extra time. Is the dog, did you say is the dog still alive or is the dog passed away now?

No, we were able to control this dog's disease with palladia for about an additional 6 months, so that, that yielded a grand total overall survival time of about 2.5 years. But yeah, it was actually progressive local disease leading to rectal, impingement on the rectum and obstipation.

That was eventually the cause of this dog's death. But a great, you know, length of time to keep the dog going another 2.5 years.

That's really good quality as well. Yeah, and I think really one of the things that we've learned about managing these cases is, really there are many things that can be offered even at the time of relapse, sort of depending on where the relapse occurs, etc. So it's not a one and done by any stretch of the imagination.

And I think having, having that sort of information in place for an owner really helps them understand the value of the recheck schedule and and the, the fact that hey, it's not, it's not game over if we see disease recur, there's still a lot of things that we can offer really gives them a lot of hope. That's great. There's a question here from Alison, she's saying is palladia being used in cats at all for squamous cell carcinoma?

So Yeah, great question. So, you, you'll find nothing in the literature about either the safety or the pharmacokinetics, or the anti-tumor efficacy of palladia in cats. However, on an anecdotal basis, certainly it's known that cats do seem to tolerate, kind of the label dog dose of palladia quite well.

In fact, in my hands, I think it's tolerated a bit better than than it is in dogs. And there certainly are reports of responses in some cats with mast cell disease. There is some unpublished information actually looking at palladia in cats with squamous cell carcinoma, and unfortunately, there does not appear to be a great deal of efficacy in that disease.

Yeah, I, I think Doug, it's fair to say that, I mean, my feeling is that the squamous carcinomas in cats are very driven by EGFR and EGFR isn't a great or theoretically shouldn't be a target for the serin. Yeah, so if, if it, if it, if it looks like it does in the human disease, it does appear that at least a subset of them are EGFR driven and EGFR is not a target of Calaia. Very true.

We've got another couple of questions. First of all, we've got Lydia just saying she's enjoyed the exhibition, introduced her to some company she didn't know of. And then we've also got Jamie saying, .

Could carboplatin used post-surgery without radiotherapy for anal sac adenocarcinoma, give a favourable outcome? So, that's, that's really the million dollar question. And we, we offer it to our patients under the assumption that it may improve the outcome, but there really are no meaningful statistics or percentages unequivocally demonstrating the efficacy of postoperative carboplatin.

I would like to think that it helps, but, I'm, I can't stand up with a straight face and, and tell owners how much it helps or with, with, with, unequivocal assurance that it does. Doesn't stop us from offering it though. But you also David, use that same protocol as well.

Yes, I mean, I mean the one thing that you know, gives me some encouragement is that there have been dogs with really large lymph node disease which we've done pre-surgical shrinking using carboplatin. And that gives me some encouragement that perhaps a post-surgical management of carboplastin without radiation has a beneficial effects and you don't tend to get these dogs die from the recurrence, they tend to die from lymph node metastasis. So biologically, there's a, I think there's a very good rationale for using it.

It's just we don't have the large scale studies and the statistics to back it up. That's great. I'm conscious it is 5 o'clock, but I think, you know, it would be great to see at least one more case, Doug, if you're happy to do one more case, the benefit of webinars is that people can slink quietly out of the virtual lecture theatre and you will not be any more the wiser, but it allows people to leave sort of surreptitiously, if you like.

So, I mean, I'm certainly happy if you're happy to do one more of the cases. Sure, I'm happy to do one more. That'd be great.

OK, well, let's do that. Those of you who are going, please do go and have a look at the Facebook page and, and like it and maybe make some comments about the, about the conference. Similarly, you can retweet and Twitter to your heart's content and do go and look at the virtual exhibition.

There are some nice bits of information there and some competition prizes and so on. We have also in the chat box, put some links in for the . For the Congress for next year if you do want to buy a ticket early to benefit from the, the lower prices.

So with that, I will move back to, to Doug for his second case. Thanks everyone. Great.

Thanks, Anthony. So, the next one is an older white domestic short hair named Delaney. And Delaney actually presented for this love by the Eye.

And at the time they presented to us, so they actually presented to us essentially on first opinion. The way our service works here is we certainly are willing to see animals that have not been referred by their primary veterinarian, and in this case this was a first opinion case for us. And at the time that the, the cat was seen, you certainly may notice that there were similar lumps and crusts, etc.

Actually on the tips of both pinnae as well as this lesion on the above the, the right eye. And the owner said that this lesion, sort of in the in the area above the right eye had been present for around about a year and had been slowly progressive. And really the thing that brought the owner in was the fact that the cat had started to worry the lesion.

She had started to rub it on the floor, and, and scratch at it, which was causing ulceration and irritation. So, the workup in this case started with initially some cytology, both imprint cytology and an attempt at a fine needle aspirate. So you can see this lesion is a little bit productive.

So there was an opportunity to try and get a fine needle aspirate into that. And again, what we saw was an appearance very similar to the appearance in the last case that I show you, really granulo pio granuloinous inflammation, and not anything that would tell us really what the underlying disease was. And this is actually all too common a situation when we're trying to do imprint cytology of tumours or suspect tumours, because the top of, of the tumour is often going to be again inflammatory.

Dying cells, etc. The kinds of things that are really hard to get a diagnosis from. So this is a case where a biopsy was actually very important for confirming our diagnosis.

And when we did do our punch biopsy, in this case of the, the periocular lesion, we did, very easily obtain a diagnosis of squamous cell carcinoma. And again, that should not be a surprise. Based on the fact that this was a light-haired cat who did spend some time outside.

So again, especially here in, in our part of the country where the sun shines about 310 days a year, chronic sun exposure is obviously a major, major contributor to to this kind of disease process. This is not a disease where, where metastasis is observed often, but it's also not impossible, especially with a fairly protracted duration. In this particular case, we actually evaluated both the submandibular and the prescapular lymph nodes, and we're able to find no evidence of, of metastasis.

You might ask, why did we bother to evaluate the pre-scapular lymph nodes? Well, that actually brings up kind of a slightly interesting digression. One of our surgery specialists here, Doctor Deanna Worley, Has actually sort of carved out a niche of expertise in doing what's called sentinel lymph node mapping, which is actually injecting a small amount of either a radioactive material or a dye into a tumour and then actually tracking where that radioactivity or where that dye goes to identify what lymph node.

Drains that area. And one of the things that we've learned over the last few years, which was actually quite surprising to us, is a fair number of, of oricular or pericular tumours actually drained not to the submandibular or cervical nodes, but actually directly to the pre-scapular nodes. So nowadays, when we're actually looking to, to do staging for a dog that, or a cat that has a pericular tumour, we will try to sample those pre-scapular lymph nodes as well.

Chest X-ray, as expected, was normal in this cat, but again, that was performed, as much as, as much as for a staging test, as for an insurance policy to make sure that there wasn't any other underlying medical disease that might change how this owner chose to move forward with therapy for the squamous cell carcinomas. So, what are our treatment options for this kind of disease? So, surgery, again, for these ear tip masses is often the treatment of choice.

And again, this is what's flippantly referred to as the van Gogh procedure where actually the entire penis can be removed. Radiation therapy, especially local, what's called brachytherapy or plesiotherapy, a local topically applied type of radiation can be used. Cryotherapy and topical therapy with a drug called miquamod, which is a topical, immune stimulant, can all be considered, however, really, both radiation, cryotherapy, and topical therapy typically will only work for fairly small, fairly superficial lesions.

Once we have lesions that are deep, proliferative, or invasive, these therapies are not tremendously effective. We don't really have a good understanding about whether there is a role for chemotherapy in these patients. Some people have looked at, for example, intralesional platinum drugs, much the way that it's performed in horses, but there's not a lot in the literature to say one way or the other exactly how efficacious these are.

NSAID management of these cutaneous squamous cell carcinomas can be effective for a while. So we actually did an unpublished study. When I worked in Australia looking at meloxicam in cats with cutaneous squamous cell carcinoma.

And we were able to keep about half of cat's disease controlled for 6 months with chronic meloxicam therapy. And again, that's obviously the kind of thing in the cat that you would want to do with appropriate owner education about risks and careful monitoring of renal values. So in this cat, in this case, this cat actually did undergo bilateral panectomies, bilateral van Gogh procedures, and although it's not clear from these pictures, that periocular mass that the cat presented for initially was actually removed in total, along with, actually a partial orbitectomy.

So this eye was taken as well. And this is the cat actually about 2 months after surgery. So, I think this really brings hammers home an interesting point where I think it's, it's really critically important to have a very good understanding about the biology of the disease before talking to an owner about a procedure like this.

So I think one of the important considerations is this is a perfectly happy cat. So obviously this cat has some cosmetic deficits, but the owner wasn't bothered by it at all, and this cat has a 100% normal quality of life. The other thing that I think is really important to know is that this was a curable disease.

So this is a disease where again the metastatic potential is very low and really the major risk is local recurrence. So when we see diseases like this where a cure is achievable, we would not hesitate to be surgically ruthless. Again, with an owner that's appropriately educated and who's on board for the cosmetic changes that have the potential to take place.

So, again, the prognosis is generally excellent with these, these sun-induced squamous cell carcinomas. The largest concern that we always will warn owners about is the potential for second primaries to develop. If you think about it, the entire field of the head in this white cat has been exposed to the same amount of sun, the same amount of ultraviolet radiation.

And as a result, other parts of that face have the potential to get additional lesions in the future. And the other. Places where we're likely to see these lesions occur classically on the nasop planum and on the margin of the eyelids.

So for that reason, and not so much because of a risk of, of either local recurrence or metastasis, we do tend to see these animals on a fairly regular basis. So if we do start to see lesions occur in these other locations, they can generally be dealt with with much more conservative treatments. Again, for example, cryotherapy.

And again, catching them early is really the key to successful management. We'll typically also, caution these owners to really make some management changes at home. So if these are cats, for example, that do go outside, we'll see if it's possible to turn them into indoor cats to minimise their sun exposure.

If these are cats that tend to sunbathe in very sunny windows, we'll again, see if there are changes that can be made to pull down drapes, etc. During the sunny parts of the day, to again, do whatever we can to minimise continual sun exposure in these. Patients.

But again, the real, the real take home message in this kind of case is when we think that there's a high likelihood of, of surgical cure, we will not hesitate to be surgically ruthless, not just with tumours like this, certainly with oral tumours, with thoracic wall tumours, with limb tumours and amputation. And it all comes down again to really having a great understanding about the biology of the disease and knowing what the expectations are so that we can adequately talk to owners about the risk-benefit ratios with procedures like this. And I think this is where I will hand the microphone back to David to see if he has any additional comments and to thank Anthony again for the opportunity to participate in this forum.

Thanks, Doug. That was absolutely fantastic. And of course one close to home, of course, I think it was very careful management, you can look at these, You know, in the pre-cancerous stage, if you've got a really good owner who who perhaps spot them, you know, before there is much damage done and we can use things like have you presumably in Colorado State, I mean, it's such a, presumably a hotbed for these, do you talk a lot about using sunblock and things on the tips of the ears, or is that not something you really talk about?

You know, we, we don't, and it's probably something that's a bit more feasible in the cats on the tips of the ears than it is in the dogs with the inguinal lesions that we see because they just lick them right off. That's, that's usually our, our sort of last resort management issue. We, we'll be much more likely to, to educate owners about sun avoidance than we will about about topicals like that.

But you, you hit the nail on the head, Anthony, that, that really the key to managing these is to diagnose them early. And then you have a, a wide variety of very efficacious and very conservative treatments. It's these large infiltrative lesions that you really need to be very, very aggressive with if you're gonna be successful.

I remember seeing a lecture where I think it was an English bull terrier in Australia, which used to like to sunbathe on its back and that was of course covered with squamous cell carcinoma. So you, you, you spent a bit of time in Australia, presumably you've you've seen the same sort of things there as well, and in other states. So we see a lot of those bullies and and .

American pit bull terriers and boxers that are white, that come in with those kinds of lesions, especially in the inguinal areas. And actually in the dogs, it can be a bit more of a mixed bag. So we certainly do see the squamous cell carcinomas, but the other sun-induced tumours that we seem to see a lot more of in dogs and cats are hemangiomas and hemangiosarcomas, that also can occur in that inguinal region.

That's great, David, not as much of a problem in Edinburgh, I would guess. No, well, we do have about 30 hours of sunlight a year, . I mean, we do, we do see it actually a big problem with cats and squamous carcinoma actually the oral ones, which are a different story altogether and, and, and that those can be a real difficult tumour to manage.

I mean, we do see some of the ear tip and nasal planar ones, but it's, it's mainly in the south of England or in in hotter climates. That's fantastic. I'm, I'm seeing if any more questions have popped up, .

Just a question from Hillary, which I think is with the previous case that you showed, Doug. How easy is it to remove the sublumbar lymph nodes in a primary clinic? Or, or is this really a, a referral type case, would you be saying?

You know, I think it really has a lot to do with the, with the experience and confidence of the surgeon. So I do think that that sublumbar lymph node removal is something that, that can be taken care of in a, in a private clinic situation. I think the big issue, and again from a complication perspective, has to do with the potential for haemorrhage in these cases if these tumours are very friable.

And I think the one thing that's probably wise if these kinds of these kinds of lymph node extirpations are going to be attempted in practise setting is to make sure that blood products are available. Mhm. Yeah.

And certainly don't let a dermatologist or or an oncologist have a go at it, but make sure it's a surgeon. Amen. Again, Doug, thank you so much.

Of course you've got the rest of the day to look forward to in the sun. It is now very, very dark in in the UK, but, you know, I've thoroughly enjoyed the sessions and of course from, from David as well. He allows me to give him probably too much banter than I really should do, but there you go.

I think we've got away with it. It'd be battering me if it was a face to face, but this is another advantage of webinars, of course. Of course it's time for a beer in the UK I believe.

Yes, that's right, yeah, although I've decided to go on a triathlon this month, so, rather foolishly, but never mind. Well, it's 10:15 in the morning here, so it's time for a beer in Colorado as well. So thank you everyone for listening.