Clinical Management of VHL Tumors – Extrarenal Primaries | Medical Symposium 2024

[00:00] Hello everyone, we're happy to begin the full session on clinical management of VHL tumors, exorhenal primaries. And I would like to invite Dr. Shizuo Mukai from NGH that will speak with us on the minimally invasive treatment of retinal

[00:20] Thank you very much. This is my first meeting and I'm enjoying it very much and I'm learning a tremendous amount. So I am a retina surgeon and the ocular oncologist specializing in pediatrics and I used to do a lot of work with retinoblastoma, molecules.

[00:40] biology, retinoblastoma, that's where I cross paths with Orthon, Iliopol, and Mass General. I used to take care of a lot of VHL kids, then Orthon approached me and he needed someone to do the adults and that's here I am and we in over a little

[01:00] Over 10 years, we have over 100 patients with VHL. So I have no financial disclosures. So ophthalmologists often like to call this retinal capillary hemangioma mainly because hemangioblastoma sounds too much like retinal blastoma, which is a really bad malignancy.

[01:20] eye cancer in very young children that can even cause mortality. So it is one of the most common manifestations of VHL. As you know, up to 75% of cases of VHL in some of the studies. And because of that, ophthalmologists need to be involved with this.

[01:40] So it is a benign, highly vascular neoplasm, benign in terms of not being malignant, but not really benign because it can cause blindness and sometimes loss of eye. It can be sporadic, but we're going to

[02:00] talk about the VHL cases. It's often asymptomatic because the tumor for reasons we don't know will not involve the center of the retina unless it's very very late. Some of the cases are near the optic nerve but most of the cases are way

[02:20] from the optic nerve called extrapapillary and rarer cases that are next to the optic nerve and we'll show you some examples of those. So here is one that is what's called extrapapillary. It is away from the optic nerve, away from the center of the retina.

[02:40] And because of that, the vision stays very good for a long, long time, and these often will present late. So that's why it's important to screen these patients. There are some cases that are next to the optic nerve. These often grow very, very slowly, but they will start leaking at the end.

[03:00] some point and they're extremely difficult to treat as you'll see. So here's a case. I wanted to show you this case for two reasons. One, this is a 10-year-old girl that presented with a diagnosis of VHL. She had excellent vision because this is center of her vision, which is pretty

[03:20] pristine. Unfortunately, if you look at the rest of the retina, she had over 20 tumors. And in addition, she had a complex retinal detachment. And if the eye gets to this stage, even trying to preserve that 20, 30, or 0.7 million times the retinal retinitis, it's not

[03:40] 7-0 vision is very, very difficult. I think this is one of the most complex surgeries that I do. So the goal is to try to treat these early. How do we do that? We need to diagnose these early and treat early. So in terms of the eye, the goal is

[04:00] to save vision, hopefully save the eye. This is not going to spread out of the eye and metastasize. So there is a guideline from the American Ophthalmology Society on how to screen these patients. I think some of the

[04:20] is based on some of the older thinking in the ophthalmology literature about screening. So certainly examination is important. I agree that we should examine them once a year regarding things like pregnancy or even puberty. I don't think

[04:40] these tumors get progressed faster during those times. So I don't necessarily modify my screening based on things like pregnancy. We will talk a little bit about the preliminary findings of Belzude and FAN in a little while.

[05:00] So here is an older patient in her 60s. You can see in the left the nerve looks pretty clean. Then several years later she develops a little tumor by her optic nerve. So examination.

[05:20] In addition, the key is to do a good retinal examination by someone who knows how to look for these tumors. Unfortunately, many of the ophthalmologists, even the retina specialists, think that these tumors should be red because it's

[05:40] vascular. But they're not always red. Some of them look tan color, some of them look even pale white. So they really need to know how to do this. The other problem we have is that the newer ophthalmoscopes have brighter light. They use LED

[06:00] which is very uncomfortable. You will see if you ever get that examination done. And it's more difficult to examine patients with the newer ophthalmoscopes. I think the newer imaging modalities that we have really enhance our diagnosis.

[06:20] of these tumors. There is what's called an autovivafield fundus pseudocolor imaging. This is a type of a fundus photography, although it is not photography. It's a laser scan based on what's called a scanning laser or femascope.

[06:40] You can use the same machine to do fluorescein angiography, and I'll talk a little bit about funtosotl fluorescence after that. But the nice thing is that this machine, you can even do it without dilating the pupil. So this scanning laser ephemeral is a very important thing.

[07:00] It gives you retinal details that are not easily seen on examination often, and again, it can be done with that dilation in some cases. So I'm showing you an example of this is a normal retinal photograph on the left.

[07:20] left. You can see how restricted the field of vision is and this is one of the newer imaging technologies. So this is not the same eye. I mean it is the same eye but a different stage. You can see that if there are tumors out here, standard photograph

[07:40] you would have to sweep with many photographs, many flashes, very uncomfortable, whereas this is a single image on the right side. So the American Ophthalmological Society does not recommend fluorescence angiography, but most of my colleagues in the United States...

[08:00] states do because it will detect much smaller tumors earlier than without the angiogram. And I will show you examples of that. In addition, it's very useful in persistent or recurrent tumors. So let's

[08:20] Let's say you examine the patient and the tumor looks regressed, but you do an angiogram and you can see very active leakage, that means that the tumor is still active. With the newer machines, we can actually do the test by having them just drink the fluorescence.

[08:40] No longer is it necessary to give an intravenous injection. The downside is that there is a rare reaction to the fluorescein and there are even cases of anaphylaxis so we have to be aware of this. So here

[09:00] Here is an example. You can see there are some tumors here that are very hard to see even on examination or imaging, but you can see by fluorescein angiography there are tumors here and perhaps even one up here. Here's another instance. You can see

[09:20] that this tumor is not red, it's actually yellowish. And there's an area here with abnormal blood vessels, which is also early tumor, and a tiny spot here, all of which can be seen easily with fluorescence angiogram. And this is the same eye after treatment. You can see that the leakage

[09:40] has decreased significantly after the laser. Here's another patient with a slightly larger tumor here with lots of proliferation, which we often see in VHL patients. We had treated this, but in follow-up she has a new tumor up here.

[10:00] we needed to treat. Here is another case where this was a previously treated tumor from another center and you can see that there's probably an active tumor here because of the red, but you can't really see these little tumors very well, which can be seen well.

[10:20] with fluorescence. And this is the autofluorescence, which I'll talk about in a little bit. So this is a technique that was developed by Francois Delore in Boston. It takes advantage of the fact that the retina is transparent, but the cell layer underneath the

[10:40] general pungent epithelium, fluorescence with infrared light. How does that help in detecting tumors? Well, I'll show you. So this is the fluorescence, but the tumors in front of the fluorescence blocks the fluorescence.

[11:00] So here the tumors are pretty big so you can see it very well, but a tiny tumor you can still see with this technique. And so here's a case of extra-papillary tumor, otofoorescence-forcing angiogram, semae, inferiorly.

[11:20] So we're going to go into treatment. Again, the goal for this minimally invasive, non-surgical treatment is early treatment. And historically, I'd like to mention that in the old days, we used this.

[11:40] cut needles into these tumors from outside the eye, which was terrible. It went on to a precursor of laser photocorrelation, which was a xenon arc photocoragulator. Those are no longer available. Then, cryotherapy came available in like

[12:00] 1960s, laser in 1970s, and laser really is the best way to go. Choir therapy I use secondarily. I also use adjuvant intravitular anti-vegf. It doesn't work for the tumor, but it prevents some of the complex

[12:20] from the treatment, especially leakage, edema, and sometimes I supplement with periocular steroids. So it's really important that you treat the tumor really thoroughly the first time. And I usually do this with anesthesia.

[12:40] unless they're tiny. And, you know, certainly patients that have had multiple lasers without anesthesia will say that after you do it with laser, they say, why didn't you do that in the beginning? So I think in terms of quality of life, you prevent the pain, but you

[13:00] you also prevent multiple laser sessions. So I would recommend that. In terms of small tumors, there's a 100% regression rate if they're tiny. So again, I like to do it thoroughly from the start. Unless they're tiny, I usually do it with anesthesia.

[13:20] anesthesia, and the adjuvant treatment is to try to prevent the others. This is how I teach the laser. Here are small tumors. This is another kind of laser. I'm just going to skip those. And again, I showed this before and after treatment. They look like that.

[13:40] I wanted to show you this picture because even though this patient has had multiple tumors treated, vision stays 20-20 or 1.0 because the center here is in very good shape. Chiotherapy I usually

[14:00] use it as a second line. I usually do laser first. Then if the tumor is big enough that it needs additional treatment, I would do the cryotherapy. If you do it this way, it prevents some of the leakage and the complications. I'm not going to go into that.

[14:20] to the other types of treatment for the dynamic therapy was also developed in Boston. It is used in many of the countries, although it's often used for these tumors that are right next to the nerve. This tumor really doesn't need to be treated.

[14:40] The tumors that we need to treat next to the nerve are the ones that cause leakage like this, but this one did go on to leak. And after eight sessions of photodynamic therapy at another office, you can tell it didn't really work. Radiotherapy.

[15:00] We develop proton radiotherapy for many of the eye tumors in Boston. My boss, a mentor, Evan Grigudas, has 50 years' experience with radiotherapy, proton therapy, for eye tumors, and he tells me it doesn't work for VHL, so we don't do it.

[15:20] In terms of the Velsutifan, I've talked to Dan Gombos and other colleagues. We're a little skeptical of the results from Emily Chu. I see some of these cases both on study and off.

[15:40] And we have seen some responses like this one where the tumor, this is a tumor here, have gone away, but we also have seen cases when new tumors have arisen on the drug. So again, my approach is that laser for...

[16:00] is the mainstay of non-surgical treatment, all these other things. It's secondary. One more comment about the Belzude fan. So I've never recommended the drug for just an old person.

[16:20] ocular indication. Where I might is, let's say the patient has only one seeing eye and a vision-threatening lesion. Would the patient be willing to take a risk in using the drug? Well, I do have a patient that

[16:40] was treated for diabetes many, many years ago and the only choice for her was pituitary ablation by neurosurgical procedure. And it did arrest her vision, decline, and I asked her, would you do it again? And she said she would.

[17:00] You know, vision is such an important thing for many of the patients. So we might consider using the drug in such a case. So this is my email. If anyone wants to send me a note, I'll be happy to respond.

[17:20] We have time for a few questions. Dr. Leopold. So we hear kind of a lot of enthusiasm about

[17:40] of the Bellis Utifan and the Rednall and Geomas from Emily's work and the paper that has been presented here. You sound more reserved and other than being the future of a personality. What are the reasons?

[18:00] that you found more reserved about the retinal lesions? Well one, because I've seen cases where the patient on the drug has developed new tumor, then it's a small study that's been done.

[18:20] And it took a long time to get published. I heard her report about this many years ago. Then the paper only came out recently. So during that gap, the ophthalmologists were wondering what was going on. So one other thing for the colleagues is maybe now

[18:40] that we have a larger number of patients treated in actual rhythm of the classic protocol, then maybe ophthalmology needs to be involved right from the beginning and, you know, assess, like the rest of the tumors, as is also the response of the retinal humangioblast.

[19:00] of us. You mean we need data? Yes, I agree. So don't get me wrong. I think there are certain cases that I would recommend this drug. I think the ones that I would recommend happen to be, you know, getting the drug for other

[19:20] reasons. So if there is an indication by eye only, I think that's a different, more difficult issue. And that's why I gave the example of the diabetic woman because she was willing to take any risk to preserve her vision.

[19:40] And in the US, you know, driving is such a big deal. So, you know, vision issues is big, big deal. The other thing is if you lose the eye, either because it's ugly or because we have to remove it, it has a tremendous psychological impact on Americans.

[20:00] patients. If we don't have any other question or maybe we do. One last question please. Thank you very interesting presentation. My question is about treatment-resistant tumors. I'm a patient, I've had

[20:20] had three retinal surgeries in two years in the attempt of preserving some vision in my right eye. And I'm always wondering at what point does the disruption of the continuous surgery, the retinal detachment because of the treatment-resistant tumor, outweigh the potential of the retinal surgery?

[20:40] potential preservation of vision. So if we see these eyes early, we can certainly preserve the vision. So it's difficult when retinal detachments happen because there are three different ways that retinal detachments happen.

[21:00] And in VHL, it's the combination of all three things that cause the detachment. So you can get holes in the retina, you can get membranes that pull on the retina, and you can get leakage from the tumor. And if you have all three of those, it's very difficult surgery. And as I said before, it's one of the most

[21:20] complicated surgeries that we do. We do do aggressive surgery including removing some of the larger tumors intraoperatively. I think if it's one eye that's bad then I would only do maybe two or three surgeries then after that I would not do.

[21:40] If it's the only eye, I'm much more aggressive. Dr. Sivinafz please if you can very briefly ask. Very quick comment. Yeah. So I am a little concerned about, you know, the difference of opinion I'm hearing from various ophthalmologists about eye effects.

[22:00] Obviously this is an issue that we need clarity on. So I also heard some skepticism about how long it took to get the paper published. I'm hoping that's not driving the difference of opinion. What can we do really to make sure that the field acts as one here? Would it help to get, you know, although I was

[22:20] formulg

[22:40] Okay, so two things. One, I think we need to review our data, which I haven't done yet. The other is the ocular oncologists don't get along as well as the oncologists. Oh my God. You know, it's very true.

[23:00] look at the retinoblastoma group and we try to do, you know, studies and things, we were never able to do good study even for chemotherapy for retinoblastoma because we can never agree.

[23:20] I believe we won't solve this issue today. No, we won't. We can try. Maybe not today, but I think it's an important issue to solve. I mean, I think. I think it'd be nice to get a group of us together one way or another and modify the recommendation that the American.

[23:40] Academy made. I think the oncologists who work very closely together will try and figure something out for that for most. We see even closer that one. Dr. Mukai, thank you very much.

[24:00] Let's move now to the next talk. So Dr. Citi Boina, we talk about the CNS, the role of surgery in the modern era. I remember that Citi Boina, I remind you that Citi Boina is professor at the NIH in neurosurgery.

[24:20] Thank you. Thank you very much. It's a real pleasure to be here and I can assure the audience that neurosurgeons are a little bit closer. I was talking to Alberto before, so I think we will be more in line with each other's recommendation than ocular oncologists, but we'll see, okay? So anyway, so my name is Prashant Chiriboyna and I am a neurosurgeon.

[24:40] my day job. I also run a lab. This is where I work. This is I work with my dear friend Ram and the rest of the NIH colleagues and today we're going to talk about the central nervous system manifestations of von Hippel and Dowel disease. Specifically we're going to focus on hemangioblastomas.

[25:00] And then we'll see, you know, how the practice has changed in this modern era. The modern era being defined as post-2021 since the onset of bazudafan and the use of bazudafan amongst our patients. So just a little bit of history. The NIH has been taking care of patients with von Hippel endow disease for a very long time.

[25:20] time the central nervous system program was initiated by Dr. Edward Oldfield along with Marcelin Nehan from Urology and was taken over by Russ Langer who hired me to come to the NIH and right now I work with Mark Ball as the urology surgeon Emily Chu from Ophthalmology and then I take care of the patients with.

[25:40] centronovus system disease. So talking about centronovus system disease, what do we have? We essentially have a retinal hemangioblastomas. I is a part of the centronovus system to many of the clinicians. Endolymphatic sac tumors, we're not going to talk about that today, but we will talk about the hemangioblastomas, a vast majority

[26:00] of which are cerebellar, followed by spinal cord and then brainstem, and very rarely will have supratintorial hemangioblastomas. So what is the basis for some of the recommendations or what is the basis for our experience? The experience, the basis lies in the natural history study for patients with

[26:20] CNS hemangioblastomas that we've been running for a very, very long time and that is an ongoing study. We have 250 participants. It's not recruiting, but it is still active and that has led us to some really key findings and lessons that we've learned over

[26:40] over the last 20, 30 years, one of them is that hemangioblastoma growth can be unpredictable. It can be stochastic. So we will not know which hemangioblastoma will grow amongst all of these hemangioblastomas, for instance, in this patient, and how it will grow.

[27:00] The second key lesson is that unlike kidney tumors, size doesn't matter. What matters is symptoms. If a hemangioblastoma is causing symptoms, it doesn't matter what size it is. That is the indication to do something. And often that do something is surgery. I will talk about what.

[27:20] other things we can do. And then the key lesson number three is surveillance and patients, especially on the side of the clinicians, is actually really, really critical. If we patiently wait for the hemangioblastomas, even growing hemangioblastomas,

[27:40] To present themselves with symptoms, we find that we can actually spare our patients a number of additional surgeries, and the numbers are for additional surgery for every 10 years, rather than just going in and trying to take out every single growing hemangioblastoma. And the reason for that is that that's the castasity that we take.

[28:00] talked about, which is hemangioblastomas can change their growth curve, their growth characteristics. When they're growing, what happens to them? Three things can lead to symptoms in hemangioblastomas. Tumor growth, which is actual volumetric increase in the

[28:20] tumor size. The second thing is swelling in the surrounding brain. That can actually change the volume that is in the intracranial, the box that we have where the brain lives, or it can form cysts. Now in all of these three conditions, what happens is there is a critical volume that is crossed either by swelling or the tumor or the cyst that leads to symptom formation.

[28:40] because suddenly the pressure starts rising. These are some examples, 2017, 2019, so that's two years, and we can see how the tumor grew in the span of two years. So this is, at this point, this was an indication to surgery because the patient was symptomatic from the cerebellar, low cerebellar tumors.

[29:00] Another reason to intervene and to do surgery is the formation of pseudocyst. Now I'll be very precise here. This is not a cyst. This is not like the renal cysts because what lines the cysts in the brain is nothing. It's just gliotic tissue, which means just the fibrosis of the brain. So really, only thing we have to take out is just that.

[29:20] a mural nodule or just that tumor. There is no tumor cells in the cyst surrounding this mural nodule. So this would be an instance where we would need surgery because the patient was symptomatic. And this is another view of the same patient. Going through the axial view, as you can see, the tumor lights up on the

[29:40] flare image followed by formation of a cyst. So we can see edema precedes cyst in many, many cases. So that is another lesson that we have learned over time. And then of course this is medicine, so there's always atypical cases and one of the atypical cases that we suddenly sometimes find that unfortunately

[30:00] need surgery is that there is cyst inside the tumor. Now this is a case where the entire cyst is formed of tumor cells. And lastly, we also have very rare instances of clear cell renal cell carcinoma metastasizing to hemangioblastoma. So we've also seen those instances. But these are fairly rare.

[30:20] rare. So over the last, I would say, 10 to 15 years, we have advanced our surgical techniques, our patients are doing better. I feel that with the use of modern technology, including using microscopes and neuro navigation and modern analogistic techniques, our patients seem to be doing a lot better.

[30:40] than before, but it's still surgery. Some of the advances that we made are in removing hemangioblastomas from the spinal cord, from the brainstem, large tumors from the spinal cords. And what do we do with the tumors is that we've been able to take some of the tumors to the lab and have been able to

[31:00] derive some key findings about why some tumors grow, why some don't, and what can we do. This is one of the studies that we had completed about five years ago, and this was a window of opportunity study where we had administered our patients vernostat, and these were patients specifically

[31:20] with a germline mistense mutation and we found that it indeed rescued our mistense VHL protein. So these are the kind of studies that we were able to do with the studies with the tissues that we derive from the patients. Now just to summarize the kind of surgeries that we've needed to do over the last 10 years for our patients.

[31:40] with von Heppelin-Dow disease, specifically post-centronovus system tumors, about 371 over 10 years. This is just a summary. Vast majority of which were hemangioblastomas. A few of them were ELSTs and then very rarely microcystic adenomas, which are typically in the front.

[32:00] synapses. And a majority of the hemangioblastomas are arising from the cerebellum. Now if you increase the baseline and we go back to 1995 and let's just plot it and see what happens. What we see is that in the recent past, starting about 2021, we've had a decrease in the number of surgeries.

[32:20] decreased to below about 20 or so cases a year, which for our center is actually one of the smallest cases that we have done in a couple of decades. And why has that been? Bozodifin. However, some patients, as you can see, still need surgery for central nervous system hemangioblastomas.

[32:40] We went back and asked, especially when Josh reached out, Josh Mann from VHL Family Alliance, he reached out and he said, would you like to talk about how the surgeries have changed during this era? I was like, yes, I'd love to look at that. So I looked back and saw and asked the question, why do patients still need surgery? Because we know that balsutofan works really, really well.

[33:00] really well for centronovus system hemangioblastoma. So it turns out a majority of the patients do not have access to bazudafen, the ones in our cohort. Many of them are international patients, but many of the American patients are either uninsured or underinsured. So keeping those aside, we asked which are those patients that have access

[33:20] to balsutofan and still needed surgery. So it turns out some patients needed to stop balsutofan, either for disease progression in other organs, so for instance, kidney, or they had to stop for, let's say, starting a family. And that has happened a couple of times in one of my patients.

[33:40] been a small set of patients that have been intolerant to even the reduced dose of balsutofan, and that has resulted in symptomatic hemangioblastomas in at least a couple of my patients. And then the last category is tumor breakthrough. And I'm talking specifically about hemangioblastomas that needed surgery because the

[34:00] hemangioblastoma was not responding to the basutofen. So I went back and looked at that and it turns out, in every single one of those cases, it is the tumor-associated cyst or pseudocyst that was the cause for this breakthrough. So this is a case of a young gentleman in his 30s

[34:20] presented approximately two months after starting bazurofan with symptoms that were related to increasing size of the tumor-associated pseudocyst. And you can see this is the neural nodule, this is the cerebellum, and that's the eye, that's the back of the head. So we were able to successfully resect the surgery. Fortunately.

[34:40] Basically this tumor was very peripheral, the patient did really well. And now we are watching for the evolution of the other tumors that the patient has. So for instance there is a brainstem hemangioblastoma and a central cerebellar hemangioblastoma. So as we can see, as we track this tumor

[35:00] This is actually now 12 months after balsurifan. We can see that the brain serum hemangioblastoma has grown smaller and so has the volume of the central cerebellar hemangioblastoma. However, we are still concerned and are monitoring the size of the cyst that has not responded correspondingly to the tumor size. This is

[35:20] This is another case of a 40-some year old female patient of mine who presented initially with that little tumor that actually grew through balsutofen to an extent where she was severely symptomatic from balsutofen about a year after starting the drug.

[35:40] This is another patient that needed surgery for a section of these two small tumors that were not responding to bazirafin. So where we are today is that although the number of surgeries have decreased, it is not down to zero for Centrinovis system disease yet. And so there are some lessons that we have also learned.

[36:00] And along the way, which may help us figure out the treatment for some of our patients. For instance, the two outstanding questions are, Alberto is going to talk about one, which is should we treat hemangioblastoma right up front? And the second question that I keep hearing over and over again is which are the patients that really would benefit from bazudafan? If this were not.

[36:20] not a continuous option for all of our patients at all given times. So one of the things that we went back and asked, this is not published yet, is what about stochasticity? Within the given parameters of stochasticity, the sporadic nature of the growth, can we still figure something out? And it turns out, yes. Turns out tumors that are more

[36:40] than 100 cubic millimeters and have grown approximately more than 20% in volume over the last year of follow-up are probably the ones that are likely to need surgery in the next two years. So maybe that will be the kind of targeting that we'll need for bazudofen and maybe for surgery for some of our patients. And the second question that we keep asking our

[37:00] themselves is do all of my patients need gadolinium contrast? Because they get scans on an average a little more frequently than I eat once every year, and gadolinium does have its own consequences. And what we are seeing is that some of the routine imaging can be done with non-contrast

[37:20] to scans as well. So this is something that we are also looking at and we will be putting out our findings. So I'll finish a little bit early and happy to take questions.

[37:40] Professor Cittaboyna, do you have any questions? We have a couple of minutes. So if I understood you correctly, you were clarifying for us that the cells lining the cyst are actually benign cells that are in the cyst.

[38:00] are not associated with the hemangioblastoma, correct? In instances of hemangioblastoma, a vast majority of hemangioblastoma-associated cysts are actually pseudocysts. If you ask a pathologist, it is not a cyst. It's not lined by cuboidal ciliated epithelium. It's just essentially gliotic tissue. Glia is the scarring in the brain. Okay.

[38:20] And so I wonder, pathophysiologically, whether, I mean, one thing that we have seen with the hip to inhibitory is that in a subset of tumors, hip 1 gets induced. So I wonder whether the instances where you see a progression of the tumor, but progression of the cyst, it could be that

[38:40] that is induction of hip one with increased secretion of vegaf and increased permeability. Have you or are you aware of anyone that has looked into that? And broadly speaking, I mean, if vegaf were to be implicated in the pathophysiology, one might expect a bebasusimac, which as we know is a very important factor.

[39:00] use in some instances of edema could help with cyst and symptoms. Has that been tried? So, you know, this has been a question that we've been asking for a little while, which is, first of all, what are the contents of the cyst? Is it an exudate or is it a transudate? So it turns out it's a transudate, so that means it is essentially leaking plasma.

[39:20] asthma from the blood. So to tighten up the blood tumor barrier, one thing that has seemed to work briefly is steroids, high dose steroids work for short periods of time. We have not tried Bevacizumab along with our treatment therapies because that's

[39:40] been an honor indication. You know, Bevizosumab has been tried for solid tumors before without much effect. But we did look into the activation of VEGF and EGF signaling in our tumors. In general, it seems that tumors that are growing and are secreting more fluid

[40:00] seem to be having higher VEGF activity. I mean my understanding again our radiation oncologist for metastatic disease with brain metastasis sometimes after radiation we could have edema and if it's sometimes in addition to the steroids or as an alternative to the steroids they would try bevosucidin.

[40:20] So I suspect that it's based on some literature. Yes. In cases of radiation, there's probably additional local brain injury as well. So I think that this is what works really well in that context. I'm not sure how well it'll work in the context of tumors, but something to try. Right. Thank you.

[40:40] Thank you so much for your thoughtful talk. Do you have any ongoing research or anecdotal thinking behind why you think some people aren't responding to the Belzudeifin when most people are? Good question. So the answer is yes. We are looking into

[41:00] Which are these patients? Now they're very rare. I have five patients that have truly failed bazulafel. So we are looking at their tissues. Now they're also very, very small bits of tissue. So they're actually smaller tumors, which is good for the patient, but really not great to study. So we are trying to salvage our tumors and trying to see what we can do with that.

[41:20] Thank you. The very last question. Thank you very much for your presentation. I was interested about the fact that you said that there are no apparent two moral cells along the wall of the cyst. So I was wondering, in those

[41:40] selected cases that perhaps the patient cannot undergo surgery for some reason and we perform a radiotherapy or a radio surgery, that means that we should only take the moral nodule as target. That's correct. Okay.

[42:00] Although, O'Thon will tell you that it probably won't work if we just target the mirinogial. The cyst is not going to go away. I'm paraphrasing him. So. So again, I mean we don't have to assume here things that are data and they're pretty strong data. And the data say that.

[42:20] If you radiate, the nodule will respond by freezing itself for a while. The cyst will not be absorbed. So in the case that your cyst is giving you the symptoms, it's not going to improve with radiation. As a matter of fact, it will become worse with radiation because now you're going to increase inflammation.

[42:40] So if you have a critical lesion, you are going to block your for vertical and we had patients that we had to take them to surgery after radiation because they were so steroid dependent because they became cushy noid in order to avoid the Administration steroids will have taken to surgery post up giving them

[43:00] steroids. So the radiation, I mean we moved in 2024. I mean my first line of treatment is Belzudifan. Tumors that they progress through Belzudifan go to surgery. Radiation would be my last resort. Also radiation in

[43:20] young people has the danger of gliosis and development of tumors later on in life. So if I have a 25 years old with a small human, I don't do anything. They start growing the human, and they go beyond one centimeter. I'll give them.

[43:40] I would not radiate them. Now if I'm 60 years old, which I am, you know, I can by have brain to discard. So okay, I'll radiate my brain probably. But I think that all these things are taken into consideration. Actually very good comments. I'll just make one last comment, which is we reserve, as neurosurgeons, we reserve radiation for one

[44:00] one instance which is supratintorial, hypothalamic, or supracilar tumors. And that is the one case where we feel that, look, I mean our surgery is going to probably do more damage than good. So that is the one instance where we have recommended radiation ourselves. Thank you, Professor Chitabonina.

[44:20] Let's move now to the next talk. Professor Feletti, Professor of Neurosurgery at the University of Verona, we talk about the reasons for surgery upfront when facing CNS and menchodilase. Thank you.

[44:40] Thank you, Chairman. Thank you to the organizers for having me here. I have no financial disclosures. I work at an academic institution in Verona, and we have at this institution a Gamma Knife unit.

[45:00] And I'm pointing this out because when it comes to the decision what to do if you have a patient with hemangioblastomas, you have basically three options. And we must not be biased, of course, when you have to decide which option is the best one.

[45:20] for the patient. But before we can answer to the question which is the best treatment, we have of course to consider which is the clinical presentation. There is no discussion about the fact that in a situation like this, when a patient has symptoms, neurological symptoms,

[45:40] due to the hemangioblastoma, surgery is the best treatment. But what can we do, what should we do in a patient like this? Small hemangioblastomas, maybe many of them, and the patient is asymptomatic, or the patient has unrelated.

[46:00] supposedly unrelated symptoms or very mild symptoms. So we have to start from the natural history. We have heard about data in the previous talk by Professor Chitiboyne. What we know about the natural history of this disease is that

[46:20] that most of the lesions grow in the span of 10 years. But as you can see, only 41% become symptomatic. And up to 45 symptomatic hemangioblastomas are not visible at the initial MRI. And this is happening because

[46:40] Their growth rate is totally unpredictable with growth periods alternating with quiescent periods and these quiescent periods may last up to four or five years, which is a long time. And similar data were obtained also by

[47:00] our group a few years ago, we collected all the data about our population and actually we found that this interval between different evolution is quite long sometimes, about 3.5 years for cerebellar hemangioblastoma.

[47:20] We have sometimes seven years of this interval. For example, for brainstem, hemangioblastomas, or five years for many of the spinal cord, hemangioblastomas. So based on this data on natural history, what should we do for our patients? Of course, microsurgery.

[47:40] surgery is the historical treatment and these are the results with this kind of treatment. As you can see, we can obtain total resection of the nodule in more than 80% of patients and we can obtain very good

[48:00] outcomes in most of the patients. So a decreased outcome, a bad outcome, only for about 5%, 4, 5% of patients. So very good data. If you consider that these data come from patients with neurological symptoms.

[48:20] at admission. We reviewed our personal experience on 102 patients, operated on for the removal of 125 hemangioblastomas, and our results were very similar to the ones published in the literature.

[48:40] improved outcome in more than 80% of patients, stable situation, neurological situation in 12, and worsening in 6% of our patients. But the real question is when to operate our patients.

[49:00] If there are no symptoms, probably the best treatment is wait and see. This is what literature says. So if you have a patient with a mangerblastoma, the mangerblastoma can also be not negligible in its size, but the patient is doing fine.

[49:20] What we know from the natural history and from the outcome of surgery is that it's better to wait. Wait until the patient has symptoms. Of course, when symptoms appear, we have to do something and we have to remove the hemangioblastoma. And we have to be very, very cautious.

[49:40] issues in the surveillance on these patients because it's true that it's probably not correct to operate a patient if the patient is asymptomatic. But it is also true that if we wait too long, the neurological outcome of the patient will be

[50:00] much impaired, much worsened. So the literature is very clear in saying that especially for spinal cord emangioblastoma, we have to remove the emangioblastoma at the beginning of, at the onset of the symptoms without waiting too long. Of course there are some exceptions to this.

[50:20] rule. Some speakers previously pointed out that for example if hemangioblastoma in a non-symptomatic patient gives a high risk for its location, gives a high risk of CSF pathway obstruction, and

[50:40] consequently an acute hydrocephalus, then that's a good reason to operate the patient, to remove that hemangioblastoma before the onset of symptoms. But there is not only microneurosurgery.

[51:00] What about radiosurgery? Unfortunately, there are no randomized control studies comparing microneurosurgery with radiosurgery. And more importantly, there are no randomized control studies comparing radiosurgery with the wait-and-see policy.

[51:20] So it's very difficult to draw conclusions about the effectiveness of radiosurgery. However, there are some publications. If we look on PubMed and we look for meta-analysis, I could find only two of them. This is the first one.

[51:40] measuring the five year progression-free survival defined as neurodographic progression. As you can see, only 14 papers were included because only 14 papers were unbiased. The follow-up, the main follow-up is quite short, as you can see, and the pull five year

[52:00] progression-free survival was shown to be quite high. But there are some adverse effects. And more importantly, with this kind of follow-up, very short follow-up, we cannot say that this number is very different from the natural history of the disease. And the second

[52:20] meta-analysis into consideration, nine studies. Again, very nice rates of tumor control at five years. But again, the follow-up is not enough, not long enough. And actually, these authors conclude that the long-term outcome

[52:40] need further investigation and surgical resection is still the first line treatment. There is one paper with a long, quite long follow-up and this paper shows that yes, local control rates with radio surgery are high initially, but as you can see when you move on with the follow-up, they dramatically increase.

[53:00] decrease. And they conclude saying that the prophylactic treatment of imaging evidence asymptomatic tumors, whether they are growing or quiescent, so also when they are growing, is unnecessary. This is written by the people doing radio surgery. Because complete surgical resection is

[53:20] associated with absolute local control and can be performed with minimal morbidity in most of the cases. It should remain the treatment of choice for most VHL-associated central nervous system hemangioblastomas. So am I saying that radiosurgery is not useful at all? No, I'm not saying that.

[53:40] There are some cases, specific cases, when we can use this option, for example, in very fragile patients that cannot tolerate surgery and in cases of very hard-to-be-resected Imangible Astomas. I give you an example, a ventrally-located

[54:00] hemangioblastoma in the cervical or dorsal spinal cord, for example. The morbidity in that case would be very high for the patient, so we can do radiosurgery in those cases. And finally, the systemic therapy. We have heard wonderful presentations in these two days.

[54:20] And especially today, we know the history of systemic therapies for fornipolyne doubt disease with initial experiences with this kind of drugs, anti-VEGF drugs that were not so, the results were not so exciting. But now we have bezutifan.

[54:40] Unfortunately, Belzutifan is not available in Europe yet. Hopefully it will become available in the near future. It showed actually very promising results. But again, the follow-up is not long enough to be.

[55:00] like enthusiastic about this treatment. We are very, very optimistic and we hope it will be a game-changer, but we need a longer follow-up, especially because there are also some adverse effects, as we have seen. So to conclude,

[55:20] is still the first line therapy, especially in symptomatic patients and in some asymptomatic patients when the threat of the position of the hemangioblastoma is particularly challenging. But we have to be careful in selecting the product.

[55:40] proper timing, especially for spinal cord hemangioblastomas. There are no clear results of radio surgery compared to the natural history of the disease, but still we can take it as an option in fragile patients or unresectable tumors. And I really think, again, that the game-changer will come from the future.

[56:00] the bench, not from radiation. There are ongoing trials and we all hope that these new drugs will help us neurosurgeons to rest more in the future and especially to help the patients. I want to conclude thinking of course patients and their families.

[56:20] and the VHL Padova Network, which is a multidisciplinary group founded almost 30 years ago by Professor Oppokar and a special thanks also to my residents who let me out with this presentation. Thank you very much.

[56:40] Thank you so much, Professor Feletti. We have a couple of minutes for some quick questions. Do you have any experience about the...

[57:00] manchoplastoma of pituitary stock. I mean, you have taught, you have convinced us that the symptom is the cornerstone to proceed for surgery. But if we have pituitary deficiency, is this a matter?

[57:20] Yes, so of course the pituitary stalk is one of the most challenging locations for hemangioblastomas. We have seen some of them, not many actually, they are not so frequent fortunately, but there are. In those cases if the patient is in pain, then they are not.

[57:40] has no endocrine problems or no symptoms, I suggest wait and see and keep the follow-up, radiological follow-up. If there are endocrinological problems, I agree with the previous speaker saying that probably

[58:00] I would try radio surgery first, unless we will be able to have also in Europe this bezutifan, of course. Thank you, Professor Feletti. Okay, thank you. Thank you.

[58:20] Okay, let's move on with the next speaker. So it's a great pleasure for me to introduce Dr. Naris Nilubov, who is a general surgeon working at the National Cancer Institute in the US. Dr. Nilubov will go into discuss about pancreatic neuroendocrine infection.

[58:40] to more and surgical outcomes. Good afternoon. It's a pleasure to be here. Thank you, the VHS Alliance for the invitation. Excuse me. So I'm gonna talk about how we optimize surgical outcomes in hilatory pancreas neurokinetics.

[59:00] neuroendocrine tumors, which was assigned to me and to mainly focus on VHL. So the first slide, I'm going to introduce the epidemiology of the PNets. We call them from now on PNets. I'm going to talk about some syndromes associated with PNets.

[59:20] And then, you know, as a surgeon, I'm a very simple man. When we talk about syndromes associated with P-Nets, or cancer syndrome, for that matter, I need to know three things. When am I going to cut? In this case, we have to do a balancing act between.

[59:40] risk of surgery and risk of cancer metastasis, I would want to know what am I cutting? So I need to have a very good diagnostic modality that I can trust. Last, how much am I going to cut and how am I going to cut it exactly? I'm going to mention a few things

[01:00:00] about MEN1 syndrome just to show the stark contrast between these two syndromes. So for epidemiologists of PNets, we all know these tumors arise from islet cells, or langerhand. On the right, you can see CS database that shows the incidence

[01:00:20] of penins has arisen over the years for all stages, but mostly for the small tumors. It accounts for about 1 to 10% of all pancreatic tumors, mostly pendric ductal cancer we talked about. Most of these are non-functioning, and if you look at this blue arrow, penins also increase in

[01:00:40] incidence because of early detection. So there are three questions when it comes to peanuts. In fact, in any net, small bowel nets or lung nets and whatnot, is it functioning? What is the risk of metastasis? Is it associated with any?

[01:01:00] is the Haines' hereditary syndrome. So what are the hereditary syndromes associated with the P-nets? Well, it accounts for about 10 to 17% of all the patients with P-nets that we see. The most common one is Emian I. For those who do have the symptoms

[01:01:20] signs and tumors like M mean 1 but germline testing was negative. Later on they were found to have CDKN1B germline mutation and now we call them patients with M mean 1, sorry, M mean 4, of course VHL, neurofibromatosis type 1 and tuberous sclerosis.

[01:01:40] I'm going to skip most of these. We know that the peanuts in patients with VHL is about 12 to 17% and these are very common. There are subtypes of peanuts. You've heard this before. The risk stratification for low risk for field for type 1 and high

[01:02:00] of the risk of parysophia for type 2, and then the subtypes of type 2 goes by the risk of renal cell cancer. What's interesting is if you look at the HIF expression of these subtypes, the PNets for type 1, 2A, and 2B, where we can find patients with PNets quite commonly, they associate with high PNets.

[01:02:20] higher hip expression, especially type 1 where truncation of the lesion genes. This we have seen so many times today, so we're going to emphasize here that most of the PNets related in VHL syndromes are almost always non-functioning, and we stop checking any biomonitor.

[01:02:40] markers for functioning tumors. There's some reports of other cases, but most of the times, they're not quite related to VHL. It just happens sporadically just like anybody else. In terms of metastases, data from NIH showed that Exon 3 and M ixone 3 and Miscense mutation had the highest chance of infection.

[01:03:00] of metastases. Group O patients with group O blood type had higher chance to have surgeries, not necessarily metastases. The P values was not significant at that time because the core was small. But they do have higher rates of PNets and higher rates of surgery. Dr. Liburdi, back to you.

[01:03:20] then establish the side skirt in 3 centimeter or doubling time over less than 500 days would have high rates of metastases. Then Dr. Tiroch, when he was with us back then, assessed all these 175 patients with PNIDs and we found that people with 1.2

[01:03:40] centimeter or smaller tumors did not have metastases and over patients with over 3 centimeter tumors more than a third have metastases so we recommend surgery for these which is not new. More importantly patients with indeterminate I'm sorry intermediate risk tumors like

[01:04:00] 1.2 to between 2 to 3. 12.5% of those with missense mutation or exon mutation had metastasis, while those with truncated or deletions did not. So we're interested in exploring this algorithm a little bit further. Hence the current clinical trial that we have.

[01:04:20] The primary objective that we have was to assess the role of delta-tate in conjunction with patient genotype and clinical features to restratify these patients better. But more importantly, we want to explore other omics methods that we can use as a liquid biopsy shown here, all sorts of things.

[01:04:40] that we will be doing. Currently we have about 220 patients the past over two years that we enrolled and we want to enroll about 600. So the study implementation was that you know those with low risk for metastasis we're going to see them every two years and these are patients with cysts only shown here on the right.

[01:05:00] right little quadrant. Patients with P-net, no P-net after surgeries or those with the small tumors that have been stable for two years or more. In contrast, patients with higher risk, meaning those with tumors greater than 1.2 centimeter, patients will be found to have no P-net after surgery, patients with no P-net after surgery, patients with no P-net after surgeries, or those with the small tumors that have been stable for over 2 years or more.

[01:05:20] new P-net, we wanted to see them more frequently, at least for now, until we have ability to use all these data that we have to restratify them better. Patients would get CTMRI and dorotet scan every year, and the reason for CT is that we need to identify those with P-nets quite accurately.

[01:05:40] and MRI may miss small ones that aren't very clinically meaningful, but for our stratification and to assign patients to the peanut group, we need to know that, as well as the dotatate. So when it comes to patients' pancreas exists,

[01:06:00] It's very common. Now these commonly aren't amylous-rich. In other words, they don't connect to pancreas ducts. And we have not seen IPMN that we cut out in the specimen. We have seen several reports that reported IPMN. None of those that had FNA and

[01:06:20] cyst aspiration that we found to have mucin or CEA high. So we haven't really seen that other than what's in report. But more importantly though, cysts can be big and can be trouble some sometimes. But majority of them, they do not need surgery. Commonly they have what we call cyst aspiration.

[01:06:40] and they have the appearance like this. They have microcystic honeycomb appearance. And many times, they can mimic peanuts. Pathology would show that these tumors contain fibrostroma with a pithyolining in the cyst wall. We have not seen pancreatic ductal cancer arising from any of these.

[01:07:00] cyst in the cohort. We previously closed a cohort of 340 patients and currently have 220 patients. We haven't seen one yet. For example, when and what to do when surgery comes to the table of discussion, this is a young person who had big cyst that we showed earlier.

[01:07:20] She needed the access to get to the left kidney, so obviously this is in the way and she had some symptoms. So we partially removed the cyst wall she recurred and at the time of kidney surgery, we removed some more of the cystic wall and she did not recur since.

[01:07:40] In contrary, this person has a bigger problem. She's a middle-aged woman and she present with obstructive jaundice. You can see that the bile duct is all dilated and here's the reason. She did not have tumors in the pancreas, as you can see. In this case, her options would be total pancreatectomy, which would

[01:08:00] be very bloody and complicated and will give her two new diseases which pank her insufficiency and insulin-dependent diabetes so we did an updated Roux-en-Y hepatic ulcerative aginostomy and she did fine. What I don't know what to do and to this day luckily I haven't seen many of these as patients with

[01:08:20] acute on chronic pancreatitis related to cysts, because the options aren't many, and removing the entire pancreas and giving people two new diseases seems to be a little bit too much for most people, including myself. In terms of peanuts, the criteria for surgery that we outlined and discussed yesterday was patients with peanuts at about

[01:08:40] 2 centimeter in the head or the ulcerate of the pancreas, we should consider surgery. And that's because we could avoid WIPO operation and basically in-nucleate and take out lymph nodes and save most of the pancreas. And, you know, patient does not have to suffer from lifelong consequence from WIPO, which is common.

[01:09:00] than you think. And for oncologic reasons, anything above three centimeter we would do it and tumors that's growing. However, to get to the PNets, we need to know exactly if we're gonna cut out the PNets or not. And sometimes it's not easy. For example, this woman had tumors that look like this.

[01:09:20] They're not very cystic, and they're enhanced. This 71-year-old presented with this tumor at the tail of the pancreas shown here, and here's what it looks like. It's about there.

[01:09:40] Well, as it turns out, none of these is peanuts. It was dota-tate cold, and this person ended up having a splint artery aneurysm. So what we learned that FDG PET scan was very helpful. That was long before dota-tate when Dr. Sadosky was our fellow. And the kind of thing that was important to us is that we're going to be able to get the patient's health

[01:10:00] cut off that we had was anything less than 4.2, they're not peanuts. And the size is directly correlated with the SUV source of growth. Here came a long dota tape. It certainly picks up a lot of things. And compared to CT scan, we did not find the difference. Again,

[01:10:20] In the case of the samples that were small at that time, there was a study that got FDA-approved for dorticoid use in the United States. 36 patients had VHL. What we found, it detects very well for hemagoloblastoma. For imaging surveillance, we recommend MRI because the use of radiation can be.

[01:10:40] an issue for patients, young patients, who have a life, who would have lifelong exposure to radiation, and it can pick up liver lesions better than a CAT scan for the most part, or atypical penins. More importantly, that it's safe to be used in chronic kidney disease with the new generation of gadolinium. CT scan remains very

[01:11:00] sensitive for PNets and lymph node metastases if you want to detect something small, but it does come with radiation exposure and risk of kidney injury. As I mentioned before, yesterday EUS we found to be really useful. The last two that I had was a typical PNet that turned out to be metastatic renal cell disease.

[01:11:20] cancer in both cases. In terms of surgery, we would recommend inuclation if we can. In this case, we cannot because as you can see there, there are two tumors sandwiching and there's a pancreatic ductility. So this person had a Whipple. Pancreatic resection is preferred if we have.

[01:11:40] duct involvement or tail the pancreas. We can save the middle of the rest of the pancreas if we do centipancreatectomy. In terms of complications, they're not that different. So the dutch cohort is mostly sporadic. So in an isch cohort, it's mostly VHL and amine in one. We found that in inucleation versus resection had no difference.

[01:12:00] in terms of fistula, readmission, or intervention. For sure, the Dutch inspiratic case had higher rates of exocrine pancreatic insufficiency. For total pancreatectomy, we only reserved that for patients who had unsafe pancreas to reconstruct, those with big cysts that's bigger than the bowel, that we cannot connect them to the bowel.

[01:12:20] those who had existing pancreatic insufficiency. In terms of post-op, one would think that with the cystic pancreas, VHI would be independent factor associated with the exocline insufficiency. As it turned out, when we compared to immune-run inspirative cases and NIH, with the endpoint to be pancreatic insum

[01:12:40] replacement. We only found that pancreaticoid or didanectomy was the only independent factor when it comes to pancreatic enzyme replacement. And VHL only was significant in univariate analysis, but not multivariate. So WIPO does have the long-term consequence. As I said, people don't live long enough for

[01:13:00] cancer to suffer from these consequences. For the L-Sudefan, you've heard many times, I'm not going to repeat that, what I'm going to show you when we are trying to find radiographic markers to predict response, we did find in our NIH cohort, which is now about 23 patients, everybody responded at least 36 percent or 36

[01:13:20] We're trying to find a market to predict response. It turns out everybody responded very well. So I'm going to touch a little bit about amine 1. So all these syndromes that you heard before, but the stock difference between amine 1 is, you know, amine is also very common in sporadic peanuts.

[01:13:40] 40% or so, and because the tumor and the protein conmenin involves in many things mostly epigenetic regulation, to this day we don't have genotype and phenotype correlation. And it involves many pathways. I'm going to skip these.

[01:14:00] And well, so like discussed yesterday, NIs used 2-centimeter cutoff as a result because these are always multiple tumors. The recent metastasis is much higher and mostly from gastrocnoma. 2-centimeter came from the Dutch cohort that, you know, few patients are smaller than that.

[01:14:20] had liver metastasis and the French thryponase's cohort showed that it's safe to follow these patients but more importantly those with greater than 2cm had high risk of metastasis and death. You can never cure gastrocnoma so it's never a surgical disease until it metastasized either to the lymph

[01:14:40] notes of the liver, proton pump inhibitor takes care of most of the symptoms. No such thing as too high of proton pump inhibitor doses. And that's pretty much what I wanted to convey about amine 1. So you know, evidence of metastasis of penic grade and 2 centimeter, which is more or less preventative procedures.

[01:15:00] Except for a few that we had gastrocnemesis grade III. Other than that, most people do very well. And back then, we were used to play 5 centimeter. A lot of people have metastasis, so we quit using it. All right. I think time is up. So I'm not going to talk about other syndromes.

[01:15:20] Basically, they are very rare. In summary, we talked about four syndromes associated with PNets, and I talked about VHR-related PNets in terms of risk of metastases, diagnostic challenges in the role of dota-tate, treatment of cysts and PNets, and the role of melcytophan, which is very effective.

[01:15:40] I haven't been operating in peanuts related in VHL for over a year now. And I talked about immune one a little bit and here you go. Thank you. Is there any question?

[01:16:00] What do you think about the role of radiofrequency ablation in patients with a slow-growing P-net, let's say around 2.5 centimeter, instead of in one person?

[01:16:20] Yeah, honestly, I haven't had direct experience of that in the United States. Not many people do them. I know that some studies have done EOS and ablatum. So I think if we extrapolated data from liver metastases, which is the worst case of the P net, right?

[01:16:40] It controls the tumors very well. The question is how well can you ablate intra-pancuric lesions without causing pancreatitis or other complications? I don't think that you can do whatever you want to the tumor, cutting or burning for a slow growing tumor, you're going to be okay. So it becomes the balance between

[01:17:00] the risk of surgery or the risk of ablation. We haven't used them much, and I haven't seen most pancreatic surgeons do them in the United States a lot. But like I said, it should work. Thank you.

[01:17:20] So last but not least is the time for a prepare abstract. So I would invite Dr. Abrin from Sheva Medical Center in Israel. She will present a study titled, Germuline, VHL, general duration, associated with an increased risk for cardiometabolic.

[01:17:40] disease, a large population study, please. Thank you for the kind introduction and the opportunity to present this study. In this research, we had a different perspective in studying the visual gene and specifically

[01:18:00] we want to know if there are any increased risk of cardiometabolic diseases in VHL. And the reason we want to do that is because there are several pathophysiology options in VHL that can lead to increased cardiometabolic risk. First, we know that in VHL there is an upregulation of VHL.

[01:18:20] TGF transcription leading to increased angiogenesis and that the blood vessels that are formed are frail and leaky and have an increased risk of both hemorrhage and thrombosis. In addition, we know that in VHL there is erytopoiesis that can also lead to increased

[01:18:40] and further increased thrombotic risk. And Chuvash polycytemia is an extreme example of this, as patients suffering from this disease that is caused by a germline homozygous VHL variant have an increased thrombotic event risk and specifically increased risk.

[01:19:00] risk of cerebrovascular accidents that are also a leading cause of death. Finally, in V-shell, there is an increase in glucose uptake through gluteal upregulation and an increase in glucose utilization. While this increased

[01:19:20] glucosmetabolism is seemingly unrelated to cardiometabolic diseases, this study shows differently. We know that in the developing heart, during embryonic development, the heart muscle is dependent upon glucosmetabolism through glute 1.

[01:19:40] transporter uptake and that in later phases of gestation there is a shift between glycolytic metabolism into oxidative metabolism and in this study the researchers induced a conditional complete VHL knockout to the hearts of mice embryos and what they found was

[01:20:00] that this knockout blocks the shift from glycolytic to oxidative metabolism, as we can see on the right, leading to an immature cardiac structure with thin muscle wall and an underdeveloped conduction system, and these embryos eventually die.

[01:20:20] We can see that even in the tissue that is dependent upon glucose metabolism, too much of a good thing can lead to devastating effects. Again, this is an extreme example. So when taking all this data into account, our research question was, do cares of a heterozygous V-D-D cell cell?

[01:20:40] HLG invariant have an increased cardiometabolic risk. We assumed that this risk might be subtle, so we needed a large enough database. In order to try and find one, we used the UK Biobank database that includes 500,000 participants, and they were

[01:21:00] included in ages of 40 to 69 years at inclusion. And this database provides information on demographic clinical metabolic and biochemical data. And in addition, all participants underwent complete exome sequencing. And so we performed.

[01:21:20] targeted VHL gene analysis from exome sequencing data. We include only participants that had a heterozygous VHL variant, and we also excluded participants that had a variance that were classified as either benign or likely benign by a clinver.

[01:21:40] We then sub-categorized the variants according to variant severity. Low risk variants included 5-prime and 3-prime UTR variants, medium risk included missense, in-frame indels, start gain and start loss variants, and high risk included nonsense, splice eye

[01:22:00] and frame shift. We then performed a metabolic syndrome-related diagnosis to compare according to variance severity and we performed our take of a three-point MACE that included ischemic heart disease, PVD and CVD.

[01:22:20] Finally, we performed a multivariable analysis for calculating adjusting metabolic and cardiovascular risk. In total, there were about 460,000 participants in this study with complete records. Of them, 2,000 participants.

[01:22:40] 5,519 participants had a VHL variant that answered to the inclusion criteria. On the right, you can see the distribution of variants according to their severity. And below, you can see the distribution along the VHL gene, along with their classification by ClinVar.

[01:23:00] Note that most variants, the empty circles, were not classified by ClinVar. When looking at cardiometabolic diseases, we wanted to compare alcohol to what is known in the literature and we found that for diabetes, hypertension, obesity, cerebrovascular accidents,

[01:23:20] is chemical disease and peripheral vascular disease, the rates or the prevalence was similar to that reported in the literature. And when we looked at the prevalence of these diseases compared with variant severity, we found that for diabetes and CVA, the risk increased with variant severity.

[01:23:40] When looking at biochemical markers of cardiometabolic diseases compared with variant types, we found that for 5-prime UTR variants, there was a difference compared with our other variants.

[01:24:00] This five-prime UTR variant had higher glucose level, higher glycated hemoglobin levels, and a higher rate of both diabetes and pre-diabetes. And interestingly, these participants also had a younger age of diabetes diagnosis 10 years earlier.

[01:24:20] We then looked at the rate of specific cardiovascular diseases compared with variant types and we found that for five-prime UTR variant carriers, there was a trend toward increased risk of PVD but not for other cardiovascular diseases.

[01:24:40] We wanted to validate this result of an increased rate of diabetes for five prime UTR variant carriers. So we performed a multivariable analysis model that was adjusted for several confounders. And we found that indeed, all the rage at recruitment, male-stage, and non-

[01:25:00] obesity, hypertension, and dyslipidemia were associated with increased risk of diabetes. That was not surprising. However, after adjusting for all these confounders, we still found that a 5' UTR variant was significantly associated with 2 times increased risk of diabetes compared

[01:25:20] with non-carriers. So we asked ourselves, is this really a VHL-virant-related outcome? Well, in the study we did not have a direct measure of hypoxia or presyudo-hypoxia, so we used the nearest possible proxy that was available,

[01:25:40] was reticulatide count. And as you can see on the right, reticulatide count was positively correlated with metabolic syndrome-related parameters, meaning as reticulatide increased, there was also an increase in glucose, glycidine, hemoglobin, and triglyceride, and a reduction in HDL.

[01:26:00] Furthermore, red blood cell mass count, hemoglobin concentration, and hematocrit level increased with variant severity. And looking at the five prime variants, we found that they were also associated with increased reticuloid site level.

[01:26:20] To conclude, VHL variants are associated with increased risk of diabetes and cerebrovascular accidents. For the CVA risk, this could be possibly partially explained through the enhanced ertopoiesis we found in the study.

[01:26:40] increased reticulocyte count. And we also found that five prime-UTR variants were associated with an increased diabetes mellitus risk. Is this an actual cause or a possible polymorphism in this population? We're not sure. But again, the increased rate of reticulocytosis in this sub, in this.

[01:27:00] subgroup indicates that this might be a valid result. Well, the major weakness of this study is that these results are correlative and require causality validation through translational studies, but the major strength is that it is a large and thoroughly characterized cohort.

[01:27:20] I'd like to thank the VHL Alliance for their support in the study and thank you for listening. Congratulations, very, very interesting study. Is there any question from the audience?

[01:27:40] Professor Salonia, maybe? Great talk, very interesting. There is a fancy amordality, at least in Italy, over the last few years, considering GPL1 agonist to treat obese patients.

[01:28:00] Do you believe that there could be an interaction in these kind of patients using those kind of compounds which are really active in modifying the metabolism and the situation from the overall standpoint? Well, first, it's a very interesting question.

[01:28:20] And looking at patients with VHL, I first have to ask myself, do they have peanut or not? Before I answer a question regarding GLP1 agonists, because there's not a direct link, but they could be at an increased risk. Second, I think that maybe we

[01:28:40] should investigate specifically patients that do suffer from VHL and see if they do have increased obesity in the subgroup of actual patients and not such a generalized cohort and then see if such treatment might help.

[01:29:00] I have also a question. Have you evaluated if there is an early onset of the diabetes compared to the general population in this patient? Well, yes. The earlier age of the diagnosis was also compared to the general population, the non-carriers.

[01:29:20] Okay, so will these results affect the way you will do your surveillance in this patient? You will also screen for diabetes or other cardiovascular? I think it's a reasonable thing to do, first because it's

[01:29:40] quite easy to scan for cardiometabolic diseases. You can take blood tests as we do anyway to see their creatinine and their hemoglobin level. So looking at the glucose level is quite reasonable and as well as the lipid profile. And also scan for hypertension, which we do anyway.

[01:30:00] way for pheocorm and cytoma. Most of it is actually done, but you need to focus and look at it. Okay. Thank you. Thank you.