NF2 Ohio Gathering: 10-10-15



  1. Introduction of Dr. Asthagiri
  2. History of Neurofibromatosis
  3. Basics of Tumors and Finding a Cure
  4. Family Planning
  5. Diagnosis
  6. MERLIN part in current Trial Limits
  7. Tumors and Non-Tumor Issues
    • Schwannomas - Brain
    • Schwannoma - Spine and Body
    • Meningioma
    • Ependymomas
    • Eye Issues
    • Skin Manifestations
  8. Research
    • NF2 Story
    • Speed of Hearing Loss
    • VS Treatment Options
    • What Causes Hearing Loss
    • Hypothesis: Elevated Protein
    • Why Does Avastin Work?
    • VS Bone Decompression Option
    • NF2 VS versus Non-NF2 VS
    • Multi-lobulated Tumors
    • Clinical Trials
  9. Questions for Dr. Asthagiri
  10. Hearing Implant Topics from Dr. Adunka
  11. Questions for Dr. Adunka
  12. Vestibular Rehabilitation and Balance Issues
    from Dr. Harris
  13. Questions for Dr. Harris

The 2015 NF2 Ohio Gathering invited doctors to speak about NF2 with key speaker Dr. Asthagiri previously from the NF2 NIH study, now at the University of Virginia. Some of the topics included; 1. tumor issues including but not limited to 2. the difference of NF2 Vestibular Schwannoma and non-NF2 Vestibular Schwannoma biologically as well as in terms of reactions to treatments, 3. why clinical trials to date are limited, 4. Hearing Implant options, and 5. Vestibular Rehabilitation for balance issues.

1. Introduction of Dr. Asthagiri

Steve: Welcome everybody to the 2015 -- if we could all move over to the seats here. Okay, this year we have a little smaller Ohio Gathering, but it's great to see you all, all the familiar faces.

Kim: I'm deaf, is it on already? Good morning, everyone. I made a little speech here. Anyway, I am not a very good morning person at all. Better? Good. I don't look up too often when I'm reading because I lose track of the place here. Good morning everyone. I don't do speeches or introductions all that well. For our next guest, I am honored to introduce him. He is literally a cutting-edge doctor. When I first met him at NIH, I was a little leery. He actually looks too young! But upon talking to him and making sure understood what he was saying to me, I began to feel more confident in his understanding and knowledge. After a few meetings, I asked him what happens after the NIH study. He gave me the best answer by saying, if you are willing and I am capable, I will continue to treat you. And within that conversation, his amazing words to me were, and I plan on continue studying until we find a cure. That means a lot when you are a mom with a child with NF2, let alone having it yourself. As some of you know, he is no longer with NIH, but he has definitely moved into better position for the benefit of all of us. He has been awarded the Tumor Investigators Award. He is a leader in organized neurosurgery. He has served as chair of the research committee and many other accomplishments and positions. He has touched many lives already and is outstanding at trying to make a better tomorrow for all of us. Please welcome Dr. A.

Dr. Asthagiri: First of all, thanks for having me here today. That was a very introduction, even though you don't do introductions. Maybe you should start. Kim, I must say, I'm the one who is honored to have been invited. I'm very thankful for you all having me here today.

So I want to try to go slowly. But I made a conscious decision to try to have several goals for my talk today. I know that maybe some of you are seasoned veterans at meetings like this and know probably as much as I do about NF2. So you guys can go to sleep, just snore in the back, please. For the others, though, some who have children here, others who are new or have family here maybe aren't immersed in everything that all of us understand about NF2.

I'd like to get the vocabulary up to speed, show you illustrations about what we're talking about. And make sure that when you go and see a doctor or you're talking with online groups, that you are talking about the same thing. It's hard when you get on an online group and talking about apples, and the person on the other end is talking about oranges, and you finally meet and realize you weren't talking about the same thing. The same thing can happen when you go to the doctor's office, when you are talking about something and you misunderstand something.

So that's goal number one is to give an overview of NF2. Every talk I give about NF2, I do an overview, especially when are there, but also when I go to medical groups as well. Because even though it's been around for a long time, it's still in its infancy of understanding even for medical doctors. Then the second goal I want to go through is each of the different types of tumors that we deal with in NF2, not just the Vestibular Schwannoma, but also touch on some concepts about how to manage the other tumors as well.

Because I am sure that each of you have been touched or are currently going through trying to decide how to manage different things, and we'll go through that. And just sort of introduce some questions that you should be keeping in your mind as you go through things.

So a brief introduction to myself I thought I would give myself an introduction. What's most important is probably in the upper left-hand corner of this screen -- I'm an Ohio native. So these are the three teams that I loyally support. And you know one playing at noon today. If there's anybody Maryland, they can be excused right now! But I do love coming to Columbus because even the barber shop has a Buckeye sign. I was actually born in India and came to the United States when I was five years old with my parents. We grew up in northeast Ohio where I subsequently went to the University of Akron for my undergraduate. And then a medical school that's about an hour and a half from here or two hours from here called Northeastern Ohio Medical University.

After that, I went to the University of Virginia for residency. And after finishing residency, I did a fellowship, and then started practicing at the NIH back in 2006. The NF2 study there started in 2008 or 2009, and we went on and continued on that study until 2013, when I back to the University of Virginia. That's where I am now. This is my wife and two kids. So that's everything.

I wanted to let you know. It's nice to sort of touch base and talk about other things other than -- as Kim and others will tell you, many of my doctor visits with patients is about half medical and the other half is just talking about life and talking about other things that we can connect with, especially with teenagers. Connecting with teenagers and making sure that we have a good relationship that's going to stay.

2. History of Neurofibromatosis

Dr. Asthagiri: So first of all, I'd like to just touch on why are we even called NF2 and why are we lumped in with the NF1-ers. We are such an entity, NF2 is. But it really goes back to a timeline when NF2 was first described in 1822. There was a Scottish surgeon who back then they didn't really do a lot of surgeries. But a young man was losing hearing and had really bad headaches. Eventually he died. And when they did autopsy, they found multiple tumors, and wrote about that report. About 60 years later, Von Recklinghausen, a German pathologist started describing NF1. These conditions named at the time. What happened is there is a name in Neurosurgery that is quite famous and in all of medicine. He is sort of what we consider the father of neurosurgery and father of neuro anesthesiology and many other things. He said, look, NF1, NF2, they all get nerve tumors so we are going to call it Neurofibromatosis. And that's it. That's just how it stuck, meaning that we became intertwined and inseparable, even though a lot of different people have tried to rename things. So we were called Central-NF. NF1 was called Peripheral-NF. Like that it went through a lot of different naming things. But it was always just called Neurofibromatosis until the 1980s when we finally figured out that there were different genes that caused NF1 and NF2. Certainly there is a new subset of folks that are related to us as well, those are folks with Schwannomatosis. But what's most important are the three conditions are so different and represent such different types of people. And the things that they go through, it makes it very difficult when you say, I have NF, when somebody is most commonly talking about NF1.

3. Basics of Tumors and Finding a Cure

Dr. Asthagiri: So my passion is really in the management and taking care of NF2 patients. And NF1, though it is very interesting, is a lot more of a medical condition than it is a surgical condition. And so that's where NF2 represents such an important patient and condition for us to understand. In fact, those of you with NF2 in this room probably hold the key to treating a lot more people than just you in the room. So if we learn how to treat the Meningioma or the Vestibular Schwannoma or the Ependymomas that you have, we will be able to cure 45 of all brain and spine tumors among everybody in the whole United States. So even though we are a small group here, we are actually going to lead and figure out how to treat these things, and your neighbor down the street is the one who is going to benefit. Because you all are the ones who are participating in clinical trials. You all are leading the way, and they will follow, but we have to cure this first in order for everybody else to benefit. In fact, if you don't remember anything else I say today, that's fine, but I would say that part of what we need to do as NF2-ers is gain that understanding that we represent a very large community. And that the amount of funding and research that goes into helping us is not just going to help this small community, but also has the potential to impact everybody in the United States and the world. And that sort of gives you the confidence to say, hey, look, we need more money to research and try to cure this thing because we are going to help a lot of people with this. So that's NF2, and that is pretty much what I will say about lobbying and doing anything like that. But it's important to be advocates for treatment and developing new treatments as well.

So here's the background part. I am going to go through this in about 10 minutes. After you read each slide, I will pause so that we can take a look at the pictures together as well. So first of all, there's a lot of words on this screen right now. You are not missing anything, if you just read the CART for the time being, for the next couple of slides. First of all, NF2 is called a Multiple Neoplasia Syndrome. What that means is you develop multiple tumors; everybody knows that. What's unique about it is virtually all of the tumors are benign. It's caused by a mutation on Chromosome 22, which we can clearly identify with genetic testing in the vast majority of people. But just because your genetic testing comes back negative does not mean you do not have NF2. Genetic testing can only detect about 90 to 95 percent of mutations. NF2 is Autosomal Dominant inheritance. We will get into this more because I get a lot of questions with families about offspring, what are the chances that I pass this on to my children. In general, it's 50 percent.

4. Family Planning

Dr. Asthagiri:NF2 is Autosomal Dominant inheritance. We will get into this more because I get a lot of questions with families about offspring, what are the chances that I pass this on to my children. In general, it's 50 percent. But there are very special circumstances that you should understand if you're thinking about family planning, or talking to your children about family planning. A lot of us here in this room probably have children with NF2 who didn't want to come to the meeting because they are not ready to accept it or know about it. But still what teenagers do, they are involved in daily parental education. So learning about NF2 and what is the transmission patterns are very important for you all as well. Now, there is a wide phenotypic variability. Everybody who comes to me with NF2 says, I feel very lucky because.... So they are describing - they describe themselves to me. They say sometimes I feel very lucky. And this is what that means, this wide phenotypic variable, means there is a big spectrum. There are some folks who never have a single surgery their entire life and they have NF2. And so they only are discovered when they are almost 60 years old and have a little bit of hearing loss. It turns out almost everybody at 60 years old has some hearing loss. But for whatever reason they got an MRI, whether they got in a car accident or what not, and they get identified with tumors. And they are diagnosed and they have NF2. And that same condition is also used to describe one-year-olds who have hundreds of tumors with NF2. And so there's a very big spectrum.

Everybody tends to have some symptoms that develop by age 60. The most important thing to know is that 50 percent of folks will not have a parent with NF2. And so all the folks that we see, 50 percent of them, there is no family member with NF2. It's rare, you guys all know that, and when we look at the calculations, there is probably only about, even though -- I don't know there are probably 50 of us in this room, there are only about 3,000 folks, if you believe the prevalence number on the bottom, there is only about 3- or 4,000 people in all of the United States with NF2. And that's what makes it difficult to enroll in clinical trials and other things. But it's such a strong-knit community, I don't think that will be a major issue once better treatments come along.

5. Diagnosis

Dr. Asthagiri: You all know that there's different ways to get a diagnosis of NF2. You don't have to have a tumor on both balance nerves to have a diagnosis of NF2. There are different ways. So meaning that if you have multiple meningiomas, you don't have to have balance tumors. But there certainly appears to be two distinct types of NF2. One is the one that most commonly occurs, ages 20-30, and you start having some hearing loss, and that's when you recognize you have NF2. But the children with NF2 often times have problems not because of the loss of hearing that first starts, but rather because of other types of tumors like the spine tumors or the Meningiomas.

It sort of suggests even in our group of NF2 where there is one gene that sort of unites all of us, the issue is that there seems to be even in that group a lot of differences from one person to the next person. And it makes it difficult to think that one drug might cure everything. And right now where we are is trying to find a drug that cures the problematic tumors. And we have had some success in figuring that out for some of the Vestibular Schwannoma. But if I asked for you to raise your hands on how many people have tried Avastin, we all know that it works for some people and it doesn't work for other people. And like that, we need to sort of go through and figure out what is making it work in some folks and not in others.

6. MERLIN part in current Trial Limits

Dr. Asthagiri: So first of all, I do want to explain a little bit that we do understand why the gene, the same mutation in the gene, causes such a difference in what is called manifestations in some folks. So here's the gene, and this is the protein that is made. And this is called MERLIN. What happens is, MERLiN is supposed to make a circle, and then what it does is it goes and it works at different places inside of the cell. So this is one cell. This is the next cell.

MERLIN does several different things. And you'll understand why it's not -- why it is so difficult to just come out with a treatment so quickly. Because when MERLIN isn't working properly, the cells don't necessarily know where the next cell is, or that there is a cell next door. And so it keeps thinking it should just keep multiplying, because there's no boundary. Likewise, it organizes a lot of the proteins that are on the surface of the cell and so even if there are -- there's information trying to be conveyed by adjacent cells that might be misconstrued. And finally, it also affects the nucleus of the cell, that's the part that tells it when to multiply. And so there's all of these little names right here, are different proteins that MERLIN is interacting with in a different way. And so trying to - for example, if we take Avastin, Avastin works on one of the proteins on the cell surface. It doesn't do anything for the transcription inside of the nucleus. It doesn't do anything for the recognition of the next cell. That's where we are -- or that's what has gotten the clinical trials, is trying to modulate one of these interactions. Certainly Gene Therapy and other types of treatments where we actually restore normal MERLiN function seems to be a good way to restore all of these functions back to normal. And I will show you some research that we've done over the years to show that that probably is the right way to do things. But we're not quite there yet, but we're heading there.

Now, MERLiN is interesting. It's an interesting protein because it's found in all types of mammals, from small, little mice all the way up to humans and elephants. And most of it is the exact same, except the tip. And so when there is a mutation in the gene -- so this is the gene up here, and it gets changed into a protein. If you have a mutation early in your gene, that's called the conserved region. We and mice use the MERLiN for the same thing. And so if that part gets mutated, then it affects more of the core functions that it has to do. And so it cannot interact with many of the proteins. And so that's what leads to more tumors. We know that if you have a mutation, you do your Genetic Testing, and you have a mutation sort of earlier on, that might predict that you have what is called a more severe form of NF2. Likewise, there are different mutations that affect the function more than other mutations. If you just change one mutation and it doesn't change the overall look of the protein, and it's right at that tail end, those are the folks who are 60 and just have a little bit of hearing loss. So we know that there's a correlation there, and I'll show you a little bit later how we have been able to change cells and make the function of MERLiN better in cells and show that it actually changes a lot. We just have to take the next step and get it into people with NF2 for treatment. Now, there is another complicating factor.

We said that 50 percent of people don't get NF2 from their parents. So for folks who do get it from their parents, every cell in that body has the NF2 mutation in it. For those who don't, what happens is, the egg and sperm from the parents meet. And then it starts dividing. And at some point, that egg and sperm, you can see meet, at some point there is this one cell that gets the NF2 mutation. And so as that cell embryo starts growing, a proportion of the adult carries the NF2 mutation. Might be 10 percent, might be 20 percent, or 50 percent. And so that's what affects how much it manifests in that person. So that's what -- if you have ever heard of this thing called Mosaicism, people have heard that. It's like mosaic tile. It just means a certain percentage of your cells if your body have this. And what that means, though, is that you probably have a less likely chance of passing it on to your children. So if you have this condition called Mosaicism, and you only have a tumor in one ear, or one Balance Nerve, then your chance of passing it on to your children is actually closer to 1 in 12, rather in 1 in 2. Likewise, if you have this, where only a proportion of your cells are affected and you have a tumor in both ears, then your chances still are only 1 in 8. This is the reason why genetic counseling is still important and why it can impact family planning as well. But for anybody who has NF2 and has a parent with NF2, it's a 1 in 2 chance.

7. Tumors and Non-Tumor Issues

Dr. Asthagiri: So we know NF2 causes multiple different types of tumors. What's not recognized and has been more so in the past probably 5 to 10 years, is that some of the problems we get aren't tumor-related. So NF2, in addition to the pictures that I'll show you, so we all know that they cause Meningiomas, whether on the surface of the brain or the spinal canal, it causes the balance nerve tumors on either inner ear, it can cause tumors inside the spinal cord. I will show you representative of these. We do know it can independently affect vision by causing Cataracts or Retinal Hematomas in the eye. What is more recently being recognized, it can cause Peripheral Neuropathy, or foot-drop or wrist-drop or nerve dysfunction, without having a tumor that's causing it. And that's because not only is MERLiN causing cells to not divide and grow into tumors, it also has other functions. And one of theme might be very critical to letting nerves function properly. And so it's not just a tumor syndrome, it's also affecting the function of the nerves to some extent as well.

Schwannomas - Brain
So the Schwannomas are the first type of tumor that we will talk about. I am going to show some pictures of all of them and make sure everybody on the same page. And then we are going to talk about what type of new developments have happened in the management of each of these types of tumors. So first, Schwannomas, they are all the same. Just because it's on the balance nerve doesn't mean it's any different than on a Peripheral Nerve in the arm. They are all Schwannomas. And they are just named by where they are located. So the Vestibular Schwannoma, this is the MRI that you all have your own disks and looked at. This is the Vestibular Vchwannoma on either side of the brainstem. And this is the Cerebellum right here. This is the Brainstem. And these are the tumors that historically were thought to start on the nerve called the Cochlear Nerve or Acoustic Neuroma and now are known to be on the nalance nerve.

Schwannoma - Spine and Body
We will get into that topic as one of the things that is really ratifying how we should think about managing NF2. But this is a Spinal Tumor here. So this is a cross-section through the neck. You can see these are the building blocks of this spine. These are called Vertebra, the Spinous Process. You can see a tumor. The spinal cord is right in the middle here, and gives rise to a spinal nerve that goes out and operates the arm. These are what are sometimes called Dumbbell Schwannomas. They have a part that pushes on the spinal cord and compromises the spinal cord function. They have another part that is less important that goes outside of this spot. But the critical part is what is compromising other functions inside the spine. NF2-ers can get Schwannomas in virtually any nerve. I have seen this, and it's important to recognize that this can happen. I will go through some examples.

This is actually through the ribcage right here. This is a tumor on the nerve, on one of the nerves that goes under the rib. I only heard about this once after somebody had done a biopsy for Lung Cancer. So, you know, a patient with NF2, oh my gosh, this looks exactly like Asbestos Cancer. It was read by a radiologist that there is plaque on the surface of the lung. They became worried, got the biopsy and only sent the result afterwards.

Likewise, here is another tumor, in a child. And this is a tumor that is actually right next to the kidney. And this is the confusion we get with NF, without actually knowing what the manifestations of NF2 are. The doctors assumed that this was actually an Adrenal Tumor, because adrenal tumors can happen in NF1. And this tumor was labeled an adrenal tumor. But in actuality, the Adrenal Gland, you can see -- probably not see -- but it's right next to it. And so this is actually just a Schwannoma inside of the abdomen.

These are Schwannomas in the arm. You can see the thumb here and the fingers here. It's just like if I held my hand here. And these can be multiple. These are Spine Schwannomas in the lower back. And this is one of the sensory nerves of the face called the Trigeminal Nerve. These are different Schwannomas named by where they are located.

The next tumor is a Meningioma. Again, these things are fairly straight forward. They are just named where they are located. But when you have them, at least one in the brain, they are often multiple. So if you have one on the brain surface, certainly it becomes paramount of importance to make sure the spinal imaging is being done as well. So this is an example of a Spinal Meningioma, and this is a Cranial Meningioma. Now, what's important, as I said, is that if you have one, they could happen in many places. And this is not an uncommon picture of multiple tumors sort of along the fault, the mid-line of the brain. Here is a tumor that's inside the skull. That's a Meningioma in the ventricles of the brain. Multiple on the spine. We'll talk about how to manage these and when it's time to manage these.

Finally, just to get the terminology right, Ependymomas, they are these small tumors inside of the spinal cord. Ependymomas can like this, small tiny tumors. This man had images 22 years apart from the first MRI that was done in the United States, and 22 years later it looks the exact same. Other folks have Ependymomas that look like this and are causing problems. But they could anywhere along the spinal cord, and we will talk a little bit about managing those.

Eye Issues
Just so that everybody knows what the eye findings are, they go and see their doctor and say they have a Cataract. Remember, cataracts are perfectly fine if you are over age 50. If you have any children and you're wondering what is the easiest way to tell if my child has NF2, is to go see the eye doctor. Not do genetic testing, do not take them to go get MRIs and things. If your child has a cataract, you have NF2 and your child has a cataract, they most likely have NF2. And the cataracts -- this is a cataract. It's in the lens. You can imagine that if you're trying to look through the middle of the eye in the lens and you have that cataract, it's going to obscure your vision. But most of them aren't like this. This is a blow-up of this eye. You can see because you get those eye drops that are really irritating and ruin the rest of your day because you can't -- they are just useless. The reason they dilate the eye is because these are the Cataracts that are most common in NF2. They are in the periphery (spelling?). So this is a blown up view of that. And that's why many Cataracts in NF2 don't require treatment because they are not the central type. They are the peripheral (spelling?)type.

And then these are the Hematomas. These are the membranes associated with NF2. These can cause problems due to Retinal Detachments or Hematomas can affect the Retina and make it not be able to receive information properly.

Skin Manifestations
As far as Skin Manifestations go, here is another sort of -- even with my residents and some of the other attendings and a lot of medical doctors, there is a lot of confusion about NF1 and NF2. If you have never seen anybody who has NF1 and NF2, this is part of the issue, Cutaneous manifestations. When we talk about Café-au-lait, that's with NF1. Actually, it's with the general population. I have one right here. And this has nothing -- folks with NF2 do have these, but so does everybody in the world. So if you have a few of these, it doesn't mean anything. This is what is, though, these are the skin manifestations in NF2. This is a skin plaque. Another easy way to look at a young person with NF2, skin plaque, they look like small scales. They don't particularly hurt. And again, they don't have any hair or anything. But after puberty, they start having a little bit of hair. So it's almost like a hairy patch. They can be anywhere. They are about a centimeter or 2 in size. They are displaced and gently swelling the skin. So those are -- that's the pictorial part of things.

8. Research

Dr. Asthagiri: We are going to go through each of the manifestations and talk about some thoughts, research that's going on and hopefully some of the things you'll have some questions about, you'll be very intrigued by. Others will be more dull.

NF2 Story
So let's first talk about the Vestibular Schwannoma. Often times I give a little story about the images that I put up because nobody knows them. The problem is you guys know everybody with NF2. So if I tell the right story, you'll know who I am talking about. So I have to change the story a little bit, okay. But the general gist will be true. And you all can sympathize with all of these stories. But this is a musician. And she is in her 40s. And was found to have -- you know how MRI's are all backwards, right? So she was found to have hearing loss, complete hearing loss in her left ear. This is the left ear. And then went to go get the MRI for that. There is a bigger tumor here, and the person's livelihood is music, like plays in an orchestra, teaches, does all this. And the bigger tumor is on the other side, small tumor is on the left side. This is the one side with hearing loss.

Speed of Hearing Loss
So what's interesting is there were years and years where we knew NF2 meant Bilateral Vestibular Schwannoma, that a lot of folks with this condition have hearing loss and people looked at it and looked at it. And I could put a summary of everything that we ever learned about Vestibular Schwannoma probably up on this slide here, which is that most people present with hearing loss or ringing of the ear in one ear, and that it's more often how folks, young adults present rather than kids. And when we look at the historical information about what can we tell patients when they are newly diagnosed with NF2 is that your hearing is likely going to be okay for the next couple of years. But right at the end of that, I have to tell you, you still can lose your hearing pretty quickly. Your experience with your right ear isn't going to tell you very much about what's going to happen with your left ear. So pretty much I told you a little bit of information, and then just said, but that may not be true for you. And so it makes it very difficult to manage, especially new patients with NF2 when you don't have a lot of information to try to counsel with. So there are several very decent treatments for Vestibular Schwannoma.

VS Treatment Options
Historically, it was always just Surgery. Now there are in the last 30 years, there has been a lot of talk about Radiosurgery. I know generally how this community feels about Radiosurgery, but we will talk a little bit more about that. And also Chemotherapy, and we will go through this.

So when a patient with a Vestibular Schwannoma comes and they just have one, they are in their 50s, and they have one, and they get diagnosed, we think about these treatment options. And we have to put in all of the different things that as a physician that we think about. So we think about, well, how old are you. If you are 85 and we find that one tumor, we are going to treat it differently than if you're 20 and have that one tumor. We talk about how sick you are. Maybe what the patient would like to have done. Some people like to have surgery, get rid of that thing. Other people say, you're not going to touch me with a 10-foot pole. Tumor Morphology, or how it looks. What is the hearing status? If the hearing is gone, maybe it's more amenable to surgery. And what is the patient like themselves. So that's pretty complicated having all those things and thinking about all those things.

But with NF2, we have about twice as many things to think about. You know for age, we think about, is the tumor going to come back. When we think about patient preferences in folks with NF2, it's all about what their prior experience was, or what they heard on social media groups. That influences a lot about what patients think about. It's not just about what is the shape and size of the one tumor; it's about what's going on in the other ear as well. And about what the hearing is like in the other ear as well. And as far as functional status goes, the Vestibular Schwannoma are sort of the tip of our iceberg, meaning there are Spinal Tumors and Peripheral Nerve tumors and Meningiomas to think about as well. So let's go now and really think about what's going on here with the other tumor. And then we will go through some of what could explain why there's hearing loss in this ear. So, remember, this is the small tumor, which already has the hearing loss. And there is some hearing loss going on over here. So by convention, historically what many have thought is that this is a balance nerve tumor.

What Causes Hearing Loss
So this is the internal Auditory Canal right here. This is an illustration that some of the medical illustrators at the NIH have put together after about a million revisions. So but here is 7-8, the Vestibular and Cochlear Nerve. Here is the Facial Nerve. These tumors that grow on the balance nerve, on the Vestibular Nerve were thought to cause problems with hearing, presumably because there is a lot of pressure that builds up inside this bony canal. See where the dotted line is? As the tumor is growing, it's simply just compressing the adjacent hearing nerve, or Cochlear Nerve. There were some studies also done, particularly out of the House Ear Institute, only with the tumors growing and compressing the nerve, that maybe in NF2 there was a tendency to actually invade the Cochlear Nerve earlier. And that's why it's so hard to save the cochlear nerve in NF2 cases versus regular Vestibular Schwannoma. But that certainly doesn't explain our specific case that we're looking at. There is a tiny tumor there, and the person's hearing is gone. So we started trying to understand if there is this disconnect; if it's not just the size that matters, what does matter? And does size matter to some extent? And we looked at our first 60 or so patients with NF2 and started looking at trying to understand better what causes hearing loss.

We don't understand what is causing the hearing loss, it's certainly unlikely that we will be able to figure out how to treat it or prevent it. So this slide I just want to point out that there's about a good proportion of small tumor .5 cubic centimeter. That's a fairly small tumor, and greater than .5 cubic centimeters. So if we take a look, this is a graph that I will explain to you and walk you through. These are all the folks with NF2 who have tumors in that ear and had normal hearing. Each dot represents one ear and the tumor inside of it. Where the dot is, is how big the tumor is. So there were some ears with really large tumors, 25 centimeter tumors with perfectly normal hearing. There are a lot, though, with really tiny tumors with normal hearing. Then we took a look at all the ears that had hearing loss. You see there are a lot of tumors that are pretty big. See them up here? What's more important, there is a lot of very tiny tumors that are causing hearing loss as well. So why are there some big tumors without any hearing loss, and why are there little tumors with hearing loss? Certainly if you just look at the averages, tumors -- ears with hearing loss tend to be bigger than ears without hearing loss. But it doesn't explain why small tumors can cause hearing loss. And that's what we wanted to try to figure out, especially when we have that initial case that we presented where there is a tiny tumor and there is hearing loss. So when we talk to our friends and we figure out, well, how does the hearing loss happen? Again, we are not going to do a show of hands.

But every patient that I talk to, I would ask, well, how do you recollect your hearing loss to have happened? Some people report, it was just a gradual thing, it just happened over time. For others, and I have very good prospective, meaning through the years that we talked to them, every March, the hearing would go bad and then it would get about 80 percent better. And that's this black squiggly line here where the hearing would get bad and then it would improve. That would happen periodically, but the overall curve is that the hearing was getting worse. Then there are folks that remember specific events, they woke up and their hearing was a little bit worse that day, and about 3 to 6 months later without any recovery. And then there were the folks who were going along just fine, and then they woke up one day and their hearing was gone. Sudden and complete hearing loss. If we take a look, these are sort of the proportions. But if this was really, you know, a tumor just growing and compressing the next nerve, we would think a lot about shouldn't they all just have gradual hearing loss, shouldn't everybody just have some gradual hearing loss? Why would it all of a sudden go bad? Or why would it get bad and then get better? And so we started thinking about other ways in which hearing loss might happen, even though it's outside of the convention of tumor growth and hearing loss. And so we look at many things. Were people having strokes in the brainstem? Is that why the sudden hearing loss was happening? Actually, this has happened to three patients with NF2. But it is still extraordinarily rare, and they had very tiny strokes in the brainstem, which in one person did correlate with sudden onset of hearing loss. But it's not a very common reason. And they had another good reason to have a stroke. Could it be that the tumor is just getting bigger? It's just getting bigger and destroying the cochlear or the hearing apparatus. Or in other conditions, what was happening is here's the cochlea here. This is the organ that translates mechanical vibration information into an electric signal. Was there a hemorrhage inside of here that happened all of a sudden that caused hearing loss? That happens in other types of tumors. Was there some type of inflammation or other process that was going on inside of here that was causing the problem? Or were we just overlooking other types of problems like conductive hearing loss? You know, the Eustachian tube dysfunction, or is there something wrong with the canal, or is it just an ear infection?

Hypothesis: Elevated Protein
So as we started looking at everybody's MRI's, what we started noticing -- you know, I work with Dr. John BUTTMAN, who some of you may know. He is a Neuroradiologist at the NIH. And we went through hundreds of these MRI's. For anybody who went to the NIH, you know you got hundreds of MRI's. What we started noticing was that everybody with some amount of hearing loss, or almost everybody with some amount of hearing loss, always had an elevated amount of protein that could be picked up on the MRI images on specific sequences. People who come to the NIH always asked me, why does my MRI take twice as long as it used to? And these are the reasons why, is because we were looking for things that could help us predict when somebody would lose their hearing. But when we looked at the hearing loss ear, virtually all of them, 35 out of 37 had this elevated protein. You can see that it's not on the other ear. So just so that for frame of reference, there is a tumor that is sitting here, here is the brainstem. This is pointing to the cochlea, the place that I'm talking about. You can see everything is black on the other side. So when we take a look at this -- this is that same 37 people with the hearing loss.

So we said, well, almost -- ignore this part -- everybody has this elevated protein. Then we looked at the folks with normal hearing and we said, wait a minute, there's a lot of people with normal hearing in this increased protein. What can explain what's going on here? So then we started looking at folks with this really tiny tumor, and you see there is elevated protein in this ear? And in actuality, there is markedly elevated protein, even with a tiny, tiny tumor. And so we came up with this hypothesis which -- you know, I don't want to say we came up with it because it's really based on a lot of literature from the 1930s, 40s, and 70s that suggests that there is a structure out here -- see this little line right here, that actually serves a very important function. So this is the normal balance nerve and hearing nerves going into the internal auditory canal. If we put a tumor there, we know that these tumors leak proteins. That's what they do.

If any of you have ever had a Spinal Puncture or even folks with one tumor on one side, if we do a spinal puncture, we see elevated protein in that Spinal Fluid. And so these tumors are secreting this protein into the spinal fluid. This is the part that goes down into the back. But it's also secreting a lot of these - each protein is marked by one of these green dots. It's really concentrated here. And what we know is that this structure right here, where the nerves from the brainstem actually go into the cochlea is called the OSEO Spiral LIGMA. This is a little bit permeable to these proteins. If you have a high gradient of protein here, really high gradient of protein here, what will happen is the protein will eventually sort of accumulate inside of this cochlea. And so what becomes important is not whether you have a tumor or not, but whether or not it is trapping all of these proteins in this area. And so the closer that you get to occluding that size, whether it's a small tumor located very distally or it's a bigger tumor that's located here, because the hole is getting bigger, all that matter that you accumulate the protein past is where the signal is being formed.

Now, what we know, though, is that some patients with NF2 can actually get these Schwannomas inside of the Cochlea hearing erve itself, not just on the balance nerve. So these are not Vestibular Schwannoma, but Cochlear Schwannomas. And they can get them in the Vestibule as well. It gets complicated that we are only dealing with balance nerve tumors; we have to look at the MRI much more closely than that. And in fact in this person, this is probably a Cochlear Nerve Schwannoma and not a balance nerve tumor. And so, I'll show you that we have high resolution images of small tumors in patients with NF2 inside their cochlea itself. So it sort of makes you think about hearing preservation surgery and all of the things that need to be checked before we think about that. So when we look at the obstruction, or that canal and see if it's obstructed and whether that correlates with the protein, it's almost a perfect match. If the tumor prevents the spinal fluid from getting to the cochlear window, then you get this elevated protein. And what is still ongoing is trying to figure out how long the exposure needs to be before it causes hearing loss. Remember, there is a group of patients with normal hearing that have the increased protein. And the real question is whether or not these folks with that protein; 1. what is causing the hearing loss and 2. how long is it going to take for that protein exposure to cause the hearing loss? If I knew that answer, I wouldn't be doing any more research; I would have told you all and then we'd have a good predictive tool.

Once the protein has been there for two years, you better go do something about it, because next year your hearing is going to be problematic. But we are not quite there yet. But there has been a lot of support for this concept.

You know, the folks -- some of you probably know the folks at Mass. Eye and Ear Institute, some of you know them very well because our friend who is coming tomorrow, Dr. Brad Welling, is now the head of the institute. Well, the Mass Eye and Ear Institute had a doctor who passed away unfortunately within the past two years, his name was Dr. MERCHANT. And he had very nicely shown the multiplicity of tumors in this area on temporal bones that patients provided, or their families provided after they passed away. And the laboratories there have taken the fluid out of the cochlea and out of this indulin (spelling?) area and shown that those proteins can be associated with hearing loss. So I think this protein theory is gaining a lot of traction. And some of the things that we are doing that is actually working can partially be explained by this.

Why Does Avastin Work?
For example, Avastin, why does Avastin, for some people who have hearing improvement, why does it even work? Nobody can actually tell us why it works. It just randomly works. Well, if we look - it doesn't necessarily shrink the tumor, even more patients whose hearing improve, it doesn't necessarily shrink the tumor. But what we do know is that when you give it to patients with other conditions, like GBM or other types of cancers of the brain, it actually makes their blood vessels less leaky. It makes them secrete less fluid, or protein. And so one of the things that we are very interested in looking at is to see if the drug is actually in the ears that improve, are they improving because we have a good way to bring the protein down? You know, that would really support things.

VS Bone Decompression Option
Now, the other thing, especially the folks out at House Ear Institute for NF2 patients will try, if it is your last remaining ear and your tumor is filling the internal auditory canal, one of the surgeries that folks have tried is to actually go in -- don't touch the tumor, but Decompress the Middle Cranial Fossa, the canal that holds the tumor and the nerve, take the bone out around it and see if you can relieve the pressure. Historically the thought is you are relieving the pressure. But another question might be is whether or not you are just letting the fluid come in and out of that area and let it clean out the protein. That's not a long term solution. But it does seem to help for a couple years in maintaining hearing in that specific type of circumstance.

NF2 VS versus Non-NF2 VS
So the next thing I'd like to talk about with regards to Vestibular Schwannoma, which I really wonder if we are doing ourselves a disservice by calling them Vestibular Schwannoma. Because we know that they can happen on the Cochlear Nerve, like I showed you. And I'm going to prove to you here, coming up.

And we know that maybe there are multiple of them. So maybe just calling it a Vestibular Schwannoma trivializes how difficult of a problem we are dealing with. There should be some inclination to understand that the Vestibular Schwannoma in patients with NF2 are not like the Vestibular Schwannoma in the lady down the street. And the reason for that is this is the lady down the street with one tumor in the right ear. And this is NF2 patients.

If you take a look at how well Radiosurgery works for the person with one tumor, it's like gold; 95 percent or greater folks will not have tumor growth after five years after they get the Radio surgery. In patients with NF2, it's 83 percent at 50 months. Then if you go out to eight years, only half of the tumors that are treated actually will stay the same size; the other half have grown. So there's a pretty big difference between 50 and 95 percent in the effectiveness of utilizing Radiosurgery.

Not only that, but what about Surgery? Well, if you go in and take it all out, you're cured, right, in that place. Well, first of all, there's increased risks associated with hearing preservation, the chance that even if the tumor is small and we go in, it's probably 50/50 or 60/40 that we can save the hearing nerve and your hearing. The Facial Nerve preservation rate is about the same. But look at the recurrence rate, that's how often times the tumor actually comes back. Even with a complete Resection for a small tumor, the recurrence rate for somebody with one tumor is less than 5 percent. And that's over 10-15 years. If you take a look at tumors that are smaller than 1.5 centimeters in NF2, the recurrence rate 59 percent. So you thought you did everything. Ten years later they got an MRI, and there was a tumor there. Turns out -- we will get back to that in a second. But the recurrence rate is very high and different from taking out a solitary tumor.

So let's go through this. So based on a lot of conjecture, we came up with a sort of a hypothesis that we wanted to test, which was if you do have one tumor that's right here on this graph -- this is number of tumors - and treat it with that Radiation, then you have near 100 percent chance of not having it grow. But I don't suspect too many of are you gamblers, but maybe statisticians or problemistic folks. If you do the same thing over and over again, you have to keep multiplying the chance of success. So if you have a 99 percent chance of success with one event, you have to keep multiplying it. It turns out if you have five tumors in that right ear, the chance of it succeeding is around 75 percent. If you have 10 tumors, it's around 50 percent. So it keeps going, because you have to multiply .99 times .99 times .99. And so here's the odds of it working.

Multi-lobulated Tumors
So what we said was, these tumors in NF2, you have often times heard that they are like a bunch of grapes rather than just an ice cream cone. That's the difference between NF2 and a regular vestibular schwannoma, is that they look like this in NF2 patients. For Sporadic Vestibular Schwannoma, it seems to have a smooth contour. And so what we went about doing was actually going in and doing surgery; and not just going in and taking the tumor out, but also taking the tumor out, taking pictures during surgery of this Multi-lobulated picture and taking each one out and doing an analysis on each one of these independently and trying to figure out, well, are we dealing with just one tumor or are we dealing with a bunch of tumors that have grown together in this area? If there were a bunch of tumors in this area that have grown together and made what looks like one tumor, it would explain why Radiosurgery doesn't work as well, because we are treating multiple tumors not just one. It would explain why Surgery is more difficult, and it would explain why there's a 60 percent recurrence rate. Because even if you take all of this out, maybe you just leave that little tiny thing right here. And after ten years, that grows and it looks like a recurrence, but it's actually a different tumor.

So I won't go through the details, but I want to show you a few slides on what we are dealing with. This is the Multi-lobulated tumor I am talking about it. Doesn't take a genius to see that maybe this looks like multiple tumor, right? It looks like a bunch of grapes. But because we had our study start with kids who were as young as 8 years old, even before they were diagnosed with any type of hearing loss whatsoever, we were getting MRI's. And those kids that came to the study were profoundly important because they showed us by imaging where things may have come from. So you take a look here. This is the Brainstem and this is the Cerebellum. And you see here one tumor, two tumors, three tumors on the right side. This is just the right inner ear. You see a tumor inside of the Vestibule. Likewise, there are two different tumors on the left side. And so this is just highlighting each of those individual tumors. And this is somebody that we followed over the course of seven years. You could imagine if you ignore all that, you just see this, or you see one tumor, you would think it's just one tumor. But if you go back in time, you see one, two, three, four. You see that they are coalescing together. What is less distinct is starting to coalesce together. This person is only 15 years old, but you can see how it will eventually coalesce with the tumor that's here. And this is sort of beginning to prove that these multiple tumors may exist.

How often does this actually happen? What we saw was these Multi-lobulated tumors were in about 63 adult ears. And we saw that 16 of the ears had multiple Discrete tumors that we can identify. We saw that about in essence, even just by imaging, we know about 60 percent at least -- this is what an MRI can show us -- at least 60 percent of patients with NF2 probably have multiple tumors in the inner ear. And so we actually went about proving that genetically as well.

As I told you, we went in and actually took tumors like this completely out, separated them into the multiple lobules. Each lobule we sent for genetic analysis and showed that there were multiple mutations, second mutations that actually make the tumors in one side. So we know that we are dealing often times not with just one tumor, but also with multiple tumors in one ear. So these are just a list of different tumors that we found in four patients. Each patient had at least four or five different tumors in one side. So it raises the question of whether we are doing it a disservice by just calling it a Vestibular Schwannoma. It insinuates that it's a fairly straight forward condition to treat. But it's not. It's probably Multi-lobulated, maybe it has Cochlear Tumors and Vestibular Tumors, and it may have a Facial Tumor in there as well. And the other question is, what is the role of this protein? And more importantly, if it is causing the hearing loss, do we have good medications or drugs to reverse it? And why does it work in some folks and not in others? Certainly I think we understand why Radiosurgery may not be as efficacious in patients with NF2.

Clinical Trials
So there have been some drug trials, right. You all may have heard of RAP-001 or Lapatinib trials and the Avastin. The Avastin seems to have done probably the best of these. In managing these, causing tumor volume reduction and hearing improvement in about 50 percent of patients. But it's a lot to go through to flip a coin to see if it will work. But if your hearing is waning in your last good ear, certainly seems like a good opportunity. As far as the other drugs, this is the RAP-001 trial that showed some patients had a tumor reduction. But it wasn't meaningful and consistent. The same thing with Lapatinib. Some patients had some tumor reduction. Others had increase. But neither of them showed any efficacy in trying to do what we are trying to do most, which is actually improve the hearing. But one out of three is not bad for what I call first attempts. And I think that we're headed in the positive direction.

9. Questions for Dr. Asthagiri

Now, in the interest time, I'm not going to talk about Vestibular Schwannomas and hearing rehabilitation because here is an otologist here who knows about 10 times about that stuff than me. So I'll skip that. If there are questions, though, I am going to provide a PDF of this to Phyllis so you could have this. This information will be there for you if you want it so you can have some understanding what an ABI is, where it's put in, where a cochlear nerve implant is put in. Also about novel technologies in that area as well. So let me just check and see how much more time I have, real quick before we keep going. Well, unfortunately, I think I will have to pause here for a minute, Phyllis. I'd be happy to take some questions on that. Then I will figure out what's wrong with my computer here.

Audience Question: You mention multiple tumors growing In the ear canal. When you do surgery on that, are you able to tell postsurgically if it's one tumor or, say, four tumors? Are you able to pull them apart and distinguish? Or is it just all mass together as one after You remove it surgically?

Dr. Asthagiri: There are a lot of clues that there are multiple tumors there. And certainly your eye sees what it wants to see. So to be definitive about whether there are multiple tumors there, we would have to see them as discrete tumors that are not connected in any way, if you want to be a purist about things. But what I think we know, especially in NF2, is that the vast majority of tumors that have different lobules in them are probably multiple tumors. I do think whether your surgeon comes out and tells you there were multiple tumors or not, and if you read your operative note, often times it is in there, that they saw a tumor or they saw two distinct tumors or three distinct tumors. But I think the majority of them probably are multiple tumors. There are rare folks who just seem to have one tumor. Probably the same folks who are 60 and are just having a little bit of hearing loss.

Audience Question: Have any of those studies looked at the spine tumors as well, the effects of the Avastin or anything else has on those?

Dr. Asthagiri: You know, the spine tumors are much more difficult to get perfect images that are able to be correlated over time. And so it's hard to get a volume that is very accurate. And that's why they tend not to be included. The balance nerve tumors or the Vestibular Schwannoma are housed by bone, and we have good ways to calculate the volumes. And it's universal; everybody almost in NF2 has these tumors. And that's why they tend to be the target tumor for the studies. The Lapatinib trial did note that some of the spine Schwannomas showed some reduction in size. One I specifically recall was astounding. One of my patients was being treated at NYU and would come and see me periodically. And it was profound how much that tumor had shrunk with starting the Lapatinib. The issue there, though, is that that was one tumor. In other tumors, like Meningiomas in that same patient, and other Schwannomas even in that same patient, did not respond to that treatment. And that's what makes it so difficult, is that we know that the multiple tumors in an NF2 patient's body carried the same one mutation, but the second mutation can be different. And there is very likely other genes that can drive specific tumors to grow. And so it's difficult. But I think going back to your question about the spine tumor, they had some efficacy. And if you think about it, if you can even treat one, there's probably value in that. We just have to uncover why did it work in that one person in that one tumor?

Audience Question: I have a question before the genetics of this, and that is, you were mentioning there are two kinds of people, one who genetically gets NF2 from their parents and the others who are stand-alone, they just develop it. And that they are the ones, the original mutation is in their line, okay. So you said that that a person who has no parents or history in their family of NF2, that they may show the mutation in 20 to 30 percent of their genes, not in every gene, is that correct?

Dr. Asthagiri: Some people. But I'm going to listen to your whole question, then repeat it, and then answer it.

Audience Question: What I am getting at is, I heard at House Ear Clinic from one of my doctors, there is a theory of two hits. You have to have maybe a genetic propensity and then you have something else happen to you that is the second hit, quote-unquote. And then that's when you develop NF2. Is that something that you all have dealt with in your research, and is that "two-hit" theory something you believe in?

Dr. Asthagiri: So the question has to do with that concept of Mosaicism that we talked about. And whether or not the two-hit theory for development of tumors is something that makes sense. And I think that there is a little bit of confusion about things in that. Remember, when you inherit the NF2 gene mutation from your parent, every cell in your body has that mutation. But not every cell in your body turns into a tumor. And that's because the gene that you got from your other parent is also in every cell in your body. It's only in those specific cells in which a second mutation occurs to knock out both copies in that cell that that cell goes on to become a tumor. So now that's if you got it from your parents.
So what I'm saying is, what Mosaicism means is that let's say only 50 percent of your cells has the original mutation. That means right off the bat, if you get a second mutation in a cell in which the first copy is still okay, that won't go on to form a tumor. Only 50 percent of your cells are subject to this problem. I have slides on this that I can show you personally and explain to you. But that concept is true, and the only reason I brought up the Mosaicism is to make sure you understand that the 1 in 2 chance is not 100 percent true if you don't have a parent with NF2.

Audience Question: I have a quick question. Have you had a chance to look into what kind of protein that is secreted in the Cochlear Implant area? The follow-up question, have you looked into inhibitors that can block the secretion and prevent it from forming tumors?

Dr. Asthagiri: The folks at Mass Eye and Ear Institute did look and compare tumors -- the fluid, the protein inside of the fluid when you have a Vestibular Schwannoma versus if you're getting that fluid sample for some other reason. That's some other reason can be things like cochlear implantation, where you don't have a tumor. And they did find several different proteins that go along with hearing loss, like made sense for causing hearing loss. There has been no treatment or trying to alter those protein concentrations, or direct treatments for those protein aberrations. And there is no proof yet that the way that Avastin might work is by essentially reducing the accumulation of those proteins.
But those proteins that they did show, there are two of them, LRP and alpha PRESTILIN, do cause forms of congenital hearing loss. That means that you don't have a tumor, you are born with conditions with mutations in those genes, or those proteins. And they actually cause hearing loss without tumor formation. So I do think that they have very good evidence to support our story. So last year, actually it has been seven or eight months ago, we all met and discussed this. I had the imaging proof and the genetic proof about the multiplicity of tumors. Another person had the autopsy studies, and another person had the protein information, like you're asking for. But I think putting it all together is what is needed. And you're right, I think it would be great if we could reverse or stall the hearing loss because that would buy us a lot of time. And I think we stumbled on that with Avastin. And we still haven't figured out why it's working, but I think we are getting some ideas. I think that's it for questions. So I'm going to turn it back over to Phyllis, and then if there's time afternoon, I'd be happy to go through some more slides and things. But I want to make sure there is time for everybody.

Phyllis: Okay. Dr. A, thank so you much for coming. Yesterday was the first day I met Dr. A. I was never part of the NIH study. He has been terrific to work with and responding to somebody he never met before. And to have someone of his caliber and his knowledge and his commitment to come to the NF2 community, it's a real blessing that he was here. I know it's almost like a family reunion because so many of you have been a part of the NIH study.

Also this morning I wanted to recognize a couple of people who are here. We have stand up, Dr. Long-Sheng CHANG. He works at Nationwide Children's Hospital. He is involved with the CTF research project. And Sarah Burns, who is also working to help find a cure for NF2.

They seem to really enjoy our group. They came last year. They closed our dinner last year. They are coming back tonight to join us for dinner. So we are really excited about that. We are going to take a real short break and then for just a little while, we are going to have our first NF2 game challenge. And GEO is going to lead us in that for fabulous prizes! And then after that, we are going to have Dr. Adunka and Dr. Harris from Ohio State. We are going to continue along with our NF2 dialogue. So break for 10 minutes. Come on back and we will try out our game until 1:00, and Dr. Adunka and Dr. Harris will be presenting to us.

10. Introduction of Dr. Oliver Adunka

Phyllis: All righty. Our next speaker is Dr. Oliver Adunka from The Ohio State University. He is the division director for otolaryngology and neurosurgery and cranial surgery. He is in the department of otolaryngology. He is one of the most responsive and kind doctors I have ever had the pleasure of working with. You are going to love him, too. He is instrumental in making the Ohio Gathering possible this year. He went to bat for me to get money from CTF for the event. I didn't even know he was doing that. So that was wonderful. One last thing before I ass over the mic. Dr. Adunka started last October 1st at Ohio State. He came to last year's Ohio Gathering after being at OSU for less than two weeks. It was important enough for him to introduce himself to the NF2 community, and he came here and joined us last year. So I will turn this over to Dr. Adunka and Dr. Harris. It will be a co-presentation. Thank you.

Dr. Adunka: Okay, thank for having me and thank you for the very nice introduction, Phyllis. As you know, we really want to support this community especially. Dr. Welling has built such a great practice helping folks with NF2 and certainly try to fill in those large shoes and continue that kind of support. So Phyllis has asked me to speak about two things today. One is the new Auditory Brainstem Implant. And actually, there are two devices out there that I would like to speak about. And Dr. Harris, who is our fellow this year and next year, is going to speak to you about Vestibular Rehabilitation and Balance Issues with NF2.

So first I have to draw up my disclosure slide. Here it is. But really, I am going to go through all those slides. You all are very familiar with NF2 obviously, and you just learned during the tremendous presentation, more recent advancements in the disease. Again, we are attempting to understand hearing loss much better. I would certainly concur with our previous speaker that not every hearing loss we see follows this classic, what we call a Neuro Pattern, the nerve pattern. We often see patterns that we see in folks who have a more inner ear type hearing loss. That could be attributed to the protein mentioned previously.

We all know that some folks with NF2 do quite well with conventional Cochlear Implants. So Cochlear Implants some of you are an option depending on whether the nerve is viable or not, the Cochlear Nerve. The Auditory Brainstem Implant, as you most know, have been sort of the classic hearing rehabilitation option for NF2. Of course it's placed on the brainstem, as you know. The results are variable. Some folks do quite well with brainstem implants. Some folks cannot use brainstem implants. It seems to be what the tumor does to the brainstem that might have something to do with that.

So obviously we bypass the Cochlea here on the screen. We place that device directly on the Brainstem. Obviously the Cochlear Implant on the other hand goes into the Cochlea, and we require that nerve to do the heavy lifting. Which of course if that nerve is not present and in this sporadic acoustic tumor, we can save that nerve. With a lot of folks with NF2, we cannot. The ABI goes back -- there are about a thousand people who received it. These are the two people, Bill Hitselberger and Dr. House who passed away, were the people who basically came up with this. Again, about 1,000 people received that implant. And they were implanted in 1992. There was a clinical trial in the 90s as well. In 2000, the FDA approved ABI's for folks 12 years and over who have NF2. That's the only FDA-recognized approved indication for an Auditory Brainstem Implant, greater than 12 years old and having NF2. Patient selection as we know, therefore, is NF2 folks that are greater than 12. Because really if we want to implant folks that are younger or don't have NF2 but have some other nerve problem, we have to basically go through a compassionate use mechanism with the FDA, or we don't have to do that. But that's the preferred route. There are protocols when to implant and when not to. As you all know, it's very complex.

We have to sit down with you guys and really discuss if you are a candidate, which ear is a candidate. There are ways to remove tumors and put Brainstem Implants in while the hearing is still quite good on the other side. We call those Sleeper Implants. So we can turn them on if the hearing on the other side would basically drop down the road. There are various things. There is no one good protocol, typically speaking. Clinical data has suggested that the longer the brainstem has been pushed against by the tumor, the less likely the brainstem implant will work. But, again, this data are very -- it's unclear. What we currently do, and I just wanted to mention this because I know a lot of you guys have ABI's. We recently did one at Children's, which is basically a pediatric brainstem implant. There are some kids that are born without a nerve that connects the hearing to the brain. So they are born without Cochlear Nerves on both sides. Therefore conventional Cochlear Implants do not work. We have to go directly to the brainstem. And we recently did this at my previous institution at the University of North Carolina where we did -- this is our first patient there. We did five patients overall, where we were able to place Auditory Brainstem Implants in folks who do not have NF2.

So this, we are expanding this. That actually has led to a problem. Because the Cochlear Corporation has stopped producing the ABI that most of you guys have, the device that you have because they have a new device out right now. But they ran out of old devices. So what happened, this is actually not FDA approved yet. And we have to go through for every patient, through a compassionate-use mechanism. The new ABI is basically the same ABI you all have. It's packaged up differently. The internals are the same except for the housing. So this part here, this elastic housing is thinner, and it's smaller. The brain behind it is the same. It will probably be FDA-approved either late this year or early next year, probably early next year is more realistic. Right now, we are doing a few in the interim, but we have to ask the FDA for approval for each of those cases. And the reason the Cochlear Corporation ran out is because about 25 kids have received ABI's over the past two to three years that are not NF2 candidates. This is the paddle, which is virtually unchanged, the electrode that goes onto the brainstem. There is no modification. I think it works well overall.

With this process of the FDA, it's opened up the door for another ABI that has been implanted internationally, but not in the United States. And that's the Med-El ABI. Med-El is one of the three cochlear implant manufacturers, and they have had an ABI out for a long time, but never went through the process of obtaining FDA approval. The nice thing about the Med-El ABI is this paddle is a little smaller. So the part that goes on the brainstem is actually smaller in size. Other than that, it's very comparable. One advantage of this implant is, because a lot of you get ABI's, and we have to take the magnet out because you still want MRI's down the road, or you have to have MRI's. Med-El has a magnet that rotates with the spin of the MRI, and you can actually have MRI's with it, with a magnet. So you don't have to use the sticky tape. And it's genius, in a way.

So they have this incorporated in the Cochlear Implants, too. It's actually a big deal. MRI's, even with Cochlear Implants, are just a big deal. And a lot of patients are really upset that, you know, the conventional devices were limited. We are excited that we have this option right now, that we can implant an ABI without having to mess with a magnet, pretty much. It's obviously a convenience factor for you. I would argue it's a safety issue, too, in getting MRI's, and not having receiver stimulator for both devices in a similar fashion. Even on the kids we have done, we have done two and three-year-olds, it all looks very similar. It's just a little smaller. I have a little bit more difficulty of advancing that paddle on the brainstem. But other than that, it's a quite straight forward procedure. Certainly we don't have to take out a tumor, which makes it a whole lot easier.

So this is the receiver stimulator. This is the old device; as you can see, it's longer. The new device would be about two thirds of that in size. As you all know, the post-op care hasn't changed at all. It really depends on what we are doing at the same time, so if we are taking out a tumor or not. And of course we see variable results, as I indicated previously. We see some non-auditory stimulation and other things that you are more aware than I am, since most of you have gone through this. Factors that do matter is general health, obviously. Sort of timing of the ABI implantation is key, especially with respect to the tumor size and what the other ear is doing. I personally would aim for doing it sooner rather than later. There are different practice patterns whoever you are going to see for your hearing. Some folks are just more aggressive or more -- trying to put ABI's in more early for various reasons. You might not use them right then, but at least that device is placed. Some of us wait a little longer. Of course, it depends on how active you are, are you going to use your ABI. Has there previously been Radiation done and I'll agree with my colleague that we try to avoid Gamma Knife surgery for NF2 tumors. But certainly it has been done.

I'm going to skip a few of the slides. There is really not a lot of new information for you in there. I think what Phyllis has indicated, you guys are really interested in Vestibular, so balance, to learn more about how we may be able to help you in terms of balance. And Dr. Harris is our fellow this year and next year. So he really prepared a great overview, I think, of treatments we have available for you and how they might be able to help you. Before I ask him to talk, do you have any questions regarding the new devices? Any ABI-related?

11. Questions for Dr. Adunka

Audience Question: Out of curiosity, if an ABI is implanted as a child, you said the thing is smaller, what happens -- first you don't have any data now because -- what happens when the child grows into an adult? Would they have to potentially have a new implant for them that's more of an adult size? Do you have any kind of feeling for that?

Dr. Adunka: I can tell you from Cochlear Implants, because the inner ear is adult size when we are born. So we don't have to change it. They grow with the patient. The brainstem does grow a little bit and things expand. So we will have to see what happens. Usually we put a loop of the electrode lead in the posterior FOSSA behind the ear, so that can expand as the child grows. So we don't anticipate a problem, but as you said, we don't really know yet about the details.

Audience Question: If there have been multiple surgeries on the brain with removal of tumors and you have an ABI that's implanted, does scar tissue or anything from previous surgery have any effect if you put an ABI in?

Dr. Adunka: It can. Obviously the more Scar Tissue -- and Radiation does the same. So Radiation can Scar. It's interesting that some tumors that have been Radiated on, that we subsequently operated on, didn't really show a lot of scar tissue. Whereas some other ones really made taking the tumor out very hard. So it's hit and miss. Generally speaking, scar tissue, we are not happy to see scar tissue when we are in there. The less, the better.

Audience Question: Has there been a lot of success with using the ABI over? Also is it compatible with the older electrode, internal part?

Dr. Adunka: Let me answer your second question first, which was is it compatible? Yes. It's the same paddle. But the implant comes as one internal device. So if you change out the internal, you have to basically take all of it out. You have to go to the brainstem and take everything out. The externals are fully compatible. So you can take a new N6 processor and use it with your ABI. As with, are the results better? They are not; they are the same. The main advantage of the N6 ABI is that the internal part behind the ear is more sturdy. So it has not failed. Some kids who receive ABI's are not as careful as you are. And we have had actually two kids in Boston, who had to be reimplanted because the previous generation device got hit. One kid was, the brother hit it with a baseball bat, literally, and it didn't like that. So obviously it's more sturdy, it's more durable. But the brain and the device is the same, so it wouldn't make any difference.

Audience Question: Compared to the Cochlear's ABI versus the N6 ABI, do you have any preference which one to use? Regarding the Med-El ABI, when do you expect that to be more circulated in the States?

Dr. Adunka: So we just started, you know, thinking about the Med-El. There has been one Med-El ABI done in the US, and that was in Kansas City. So I haven't personally done one. Unfortunately, I don't have personal data to share. I think in the next two, three years, we will probably have the device FDA approved. Because it has been used for a long time in Europe. I think the magnet, the MRI compatibility is a huge advantage. So I don't really have a comparison personally. I could tell you that folks from Europe who have experience with both generally prefer the Med-El for kids, for smaller. The part of the brainstem that we put the ABI is called the lateral recess. And sometimes those can be quite small. The Med-El seems to fit better. On the contrary, if you have enough room, it seems that the contacts on the paddle are spaced further apart, as in the cochlear ABI, and might be an advantage. So we really don't know yet. There is no study showing that one of them is better than the other. Yes?

Audience Question: Has there been a study on tumor growth of the brainstem if the brainstem tumor has grown to cover the ABI?

Dr. Adunka: So there has not been a study. But we don't think that the ABI really causes tumor progression. So the fact that it sits on the brain or in the brain should not accelerate the growth of the tumor. There is no biological reason for that. But, again, there is no study verifying that.

Audience Question: Realizing there are lots of variables, how long after a hearing loss would someone be able to be eligible for an ABI, if the tumor has been removed?

Dr. Adunka: Right, it really depends on the other side. And that's what I mentioned previously. So let's say you have bilateral tumor, one side has no hearing and the other side still has some hearing. We would go for the tumor on the ear that has no hearing, and we could place a sleeper ABI. We could just place an ABI at that time, recognizing that there's almost 100 percent chance the other side's hearing will drop down the road.

Audience Question: What if both tumors have been removed?

Dr. Adunka: There's no ABI that's been placed in the past? Then you can place - I mean, there is no - the longer -- so duration of deafness, so the longer you are deaf, the worse ABI is going to work. So that's why personally, I advocate for placing the ABI sooner rather than later. But not everyone is like that.

Audience Question: I have an ABI implanted on my left. Let's say they need to take out that tumor because of regrowth on the left. What are the chances of being able to save the ABI when removing the regrowth?

Dr. Adunka: So the question was, if you have an ABI and then there is tumor growth that we would like to address surgically? Usually we cannot save the same ABI. What we can do in those situations, we can take the ABI out as we remove the tumor, and once the tumor is removed at the end of the case, place a new ABI. But it would be a brand new device.

Audience Question: The percentage of facial paralysis with ABI, any experience?

Dr. Adunka: The Facial Palsy or Paralysis really comes from taking out the tumor. Placing the ABI usually does not -- is not really a real risk for Facial Paralysis. The smaller the tumor that we take out, the better the chances for saving the nerve. But it's not a linear relationship. Sometimes we can save the nerve with a really large tumor, and sometimes cause facial paralysis with smaller tumors. And that comes back to every tumor is different. And sometimes the physiology works out well for us. We are smiling at the end of the day. And sometimes we really, really work hard on a smaller tumor. So the biology is what we don't have a good handle on, is what seems to influence a lot of the facial outcomes. The ABI itself should not cause facial paralysis because it goes in a different part.

Any other questions? If not, then thanks for having me, again. It's great seeing everyone. Let me know if I can help. And I'll ask Dr. Harris to give his part of the talk about balance issues. Thank you again.

12. Vestibular Rehabilitation and Balance Issues from Dr. Harris

Dr. Harris: Okay, thank you. Dr. Adunka. Thank you, Phyllis. As Dr. Adunka said, I am Mike Harris, a neurology fellow at Ohio State. Working with the NF2 community is one of the best parts of our job. It's a pleasure to be here today and I look forward to talking with you later. So we will be talking briefly about a very important quality of life issue, with is balance problems and some of the things that we can do about it in Vestibular Rehabilitation. I'll kind of use balance and vestibular interchangeably here. We will talk about where some of the key balance issues that come up in NF2 are. And really what is balance in the first place? It's a complex system. What goes into it? How do we test it? And what are some of the things we can do to work with you on vestibular problems. So you all know much more about NF2 than we do and look forward to hearing from some of you about your experiences. Balance problems with NF2 really are complex. And the reason for the complexity is that potentially all three sources of input that our brain gets about balance can be impaired or affected at some level, at some point in time.

So we can have; 1. Visual Problems including Cataracts or Eye Muscle Issues, 2. problems with input from our legs, or 3. direct impairment from the balance organ itself, coming from the tumor or from treatment related to the tumor; Gamma Knife, or Surgery itself. So really certainly can be the case that dizziness or imbalance are presenting signs or symptoms with NF2. But it's really the exception. Usually Vertigo, meaning the room is spinning, dizziness and some of the things that go along with it, nausea and vomiting, tend to emerge later in the experience, in the late stage disease.

So taking a step back, the Vestibular System, really what is it? It's a complex set of reflexes that our body has to keep us properly oriented in space. And when it's working right, it lets us do amazing things and we don't think about it much at all. It rarely enters our consciousness. When there is a problem with it, it's uniquely debilitating and can impact the Quality of Life. The simplest way to think about this complicated system is think about in terms of input and output. As I mentioned, there are three sources of input that go to our brains that keep us properly oriented. And this comes from the balance organ itself, from vision, and then from information we get from our legs. And these three sources of input feed into our Brain, the Cerebellum in the Brainstem, and they are compared and corroborated. If there is discrepancy among the three, a brain can tune down and make adjustments to keep us properly oriented. When it can't, vertigo, nausea, vomiting, that's when that sets in.

The output part of this is what we can see and it's what we use when we do balance testing. And this is manifested eye motion issues and walking, gait or standing problems. I mentioned this system is based on a number of complicated reflexes. The most important one is something called the Vestibulo-Occular Reflex (VOR). The main job of the VOR is to maintain a stable image in our eyes as we move around or as the background in our visual field moves. And this VOR is important during fast, high frequency head movements. So when you are driving a car down a bumpy road or jogging, any situation where there is movement in the background, it's the VOR that keeps us with a stable image. It's critical because when there is a problem with it, your visual acuity really goes down. Even if there's a slip of the image just as little as a couple degrees. When the VOR is not working right, the situation called Oscillopsia sets in. This comes from the faulty VOR. It's swinging vision that can range from just a mild blurring to constant jumping of the background field or of your visual field.

And it's classically seen in problems, especially in NF2 where there's tumor or treatment affects that affect both of your balance organs at the same time. One of the amazing features of the vestibular system when it works correctly, it can make these fine-tuned calibrations that we're unaware of. We don't have to think about it to fix balance problems. But in the case of bilateral or two-sided issues like in NF2, this is harder for our brains to do.

Along similar lines, some of the medications that we use that are very helpful in acute episodes of dizziness such as Antivert (medication that is used to treat motion sickness and vertigo) are counterproductive in the long term because they prevent those sensory mismatches that drive us to compensate the problems. Vestibular Rehabilitation, which I will talk about in a moment, actually forces, intentionally forces the sensory mismatches at a low level so that the brain can work towards compensating or fixing the problem.

So for anyone who has experienced dizziness or vertigo at any point in time, you know well it's incredibly frustrating. And it's hard even when you go to seek treatment for it because dizziness itself, vertigo, it's not really a diagnosis. Although we talk about it like it is sometimes. It's a symptom, a symptom of something else. And it's hard because there are many causes of dizziness and vertigo. It's also hard to explain, hard to put into words what you are experiencing. And dizziness really means something different to everybody, or can. Very uncomfortable, vertigo, nausea, vomiting are tough things to experience. And generally worse when one of those three sources of input is compromised. So in the dark, symptoms can be worse, if you are on an uneven surface, and so on.

So if you have gone to your primary care, whoever your point person is, for NF2 with issues related to dizziness or vertigo, you may find yourselves having these Vestibular Function Tests done. And the whole experience starts with just a conversation. Often history alone that you give your doctor is the most important thing in reaching a diagnosis or identifying the source of the problem. It's helpful sometimes to try to describe what you're experiencing without using the word dizziness. Like I said, it means so many different things to so many different people. Details like the onset, duration, what position you are in, and other associated symptoms are really helpful. So keep those in mind. The next step will be a hearing test and physical exam. This will include a bunch of maneuvers that may seem a bit bizarre but are aimed at learning more about movement position and walking status.

The eyes are a primary indicator of what's going on with the balance system. And a situation called Nystagmus is rapid movement of the eyes and reflects problems with the vestibular system. When we do test, we look at these saw-tooth graphs to give us information about what exactly is happening on the inside. Typically, in the case of a one-sided lesion, the fast direction of eye movement actually points to normal side. This strange looking set-up here is one way that we use to - there are two different ways that we use to look at eye motion; VNG and ENG. These are the workhorses of the vestibular testing. They track eye movements in response to a series of Vestibular or visual conditions that we put you through. And more than anything, it reflects the function of that reflex, the VOR. Using that technique for those of you who have experienced this, the most common test is something called Caloric. For this test, what we do is place warm and then cool water or air in your ear canal, usually 7 degrees above and below your body temperature to see how your eyes respond to this. This gives us information about the health and condition of your Semicircular Canals and the nerves that plug into them. It's the best test that we have for learning about sight-specific information.

The next generation in this sort of test is something called Rotary Chair. Not every institute uses this, but it is very common. And compared to the Caloric testing that we just looked at, it may better Reflect Motion experiences in our real world everyday lives. It's considered the gold standard for evaluating issues on both sides at the same time. Lastly, Posturography is an interesting test that is a measure of your balance rather than just your balance organ. It's your balance as a whole. And what happens here is that you are sort of strapped into this harness-like thing, and you are in this booth that measures based on what happens with your feature response to challenging sensory conditions. So the examiner is looking to see, did you sway? How did you shift your weight, or did you fall? You won't fall because you are attached by this harness. But looking to see how does your brain respond when the visual field changes or when the platform you are standing on shifts. It tells us which of the sensory systems you rely most on to maintain your balance.

Ultimately, it lets us tailor your Vestibular Rehab Therapy and also track your progress over time as your therapy goes on. This gives you an idea of how that test works. There are six conditions. And with each one, one of your sensory systems, or a couple of them are taken away, they are isolated so we can see how you do when you don't have that system to use to maintain balance. So for example in condition 2 here, the patient simply is blindfolded. So how do you do when your visual input is taken away? And all you have is the information from your legs and from your balance organ. Similarly in number 5, here you are blindfolded and the platform is shifting a little bit. So you have to rely entirely on your balance organ. From that, we get something that looks like this that tells us, okay, where exactly is the problem and what do we have to work on in therapy. So in this particular patient had a fall only when the Vestibular System was taken away. So this tells us a bit about how did they shift their weight on the platform, what strategies did they use to stay balanced? So then you had your testing, and the next step is Vestibular Rehab Therapy. For this, you would see a Vestibular Rehab Therapist who uses a noninvasive exercised-based approach that targets specifically some impairments like gaze instability, dizziness, and postural problems.

So what exactly is happening in your brain during Vestibular Rehab Therapy? How does it help? And it's thought to work really by three strategies: one is something called adaptation. By this, your brain makes small recalibrations or adjustments that help compensate, help fix the balance problem. The second is something called habituation. And this occurs by a series of repetitive low grade exposures to situations that make you dizzy in the first place. So that the idea being, with time, it's no longer capable of causing you problems. And then lastly, substitution, learning to use other sensory systems that do work in place, as a fill-in for those that aren't working well. The goals, of course, of therapy are to decrease or eliminate as best as possible the symptoms of vertigo, dizziness, improve gaze stabilization, and visual motor control. Ultimately, improve your balance and posture so that you can avoid falls or risk for falls.

There is also an element of learning your limits what is safe and whatnot, be safe and when you need help. And also decreasing anxiety, fear, and isolation that we know can come with balance issues.

So Vestibular Rehab Therapy is really Tailored Therapy. Not all patients with the same diagnosis have the same problems or same sets of issues. The testing we talked about will customize your Vestibular Rehab Therapy. Practically the way it works, ideally, you have one visit per week with daily exercises at home. So it really is a lot of work. Generally you can expect -- patients are told to expect improvement in around two or three months, but certainly everybody is different that way. Your primary care doctor, whoever your point person is for your NF2, may have somebody in mind as far as a therapist to refer you to. There are also some national organizations that keep a database of Vestibular Therapists you can look for in your area, and forums like this are incredibly valuable for that.

Examples of specific exercises you may find yourself doing in Vestibular Rehab Therapy, some of the most common here include the Gaze Stabilization Exercises. They sound simple, but like I said, there is a big investment of time. The goal here is to improve your vision while your head is moving. So you can maintain a stable image while you are looking at something that's moving around. Daily practice, usually about 30 minutes a day, that can be broken up over the day. It doesn't have to be 30 minutes straight. A simple way of doing this is using something like a business card in this example here. You use it as your head is stable. And over time you advance it to more challenging conditions with this exercise. Meaning you increase the speed of your head movement, you do this in background that's more and more complicated. At first you might choose a wall without much going on on it; and then with time, you might even be going outside where there is a lot of movement in the background. And then increasing with distance as well. These are more challenging sensory conditions. Posture control is critical.

The therapist typically has the patient stand still or move while they alter the three sources of input that affect our balance. So they will change the visual input you are seeing, placing a more complicated field of vision in front of you, changing the input from your legs by putting you on a more squishy surface or a surface that's moving a little bit, or both at once, to isolate the balance organ. Lastly, there is a broad set of what are called Habituation Exercises. Again these are repetitive, local grade exposures to situations that you know make you dizzy. And they target moderately stimulating motion, not necessarily those that are the most bothersome for you that over time you work up to more challenging things.

Shown here on the right, these are a set of exercises known as the Cawthorne-Cooksey (CC) exercises. They involve a series of eye movements, head movements and full body exercises that are done at home. First the therapist instructs you and then you do them at home. Those are the common exercises that you might find yourself doing.

In summary, balance and vestibular problems can affect most patients with NF2 at some point, to some degree. And really there can be a significant impact on the quality of life. Vestibular rehab is a great option that's available. It should be tailored specifically to your sets of issues, and it doesn't work right away. It can be a lot of work, but it can really improve functionality and quality of life.

13. Questions for Dr. Harris

So thank you very much for your attention. Any questions?

Audience Question: You said something about common exercises that you might be given for something. Was there a slide or something? Because I didn't see it. You didn't say what those common exercises are.

Dr. Harris: Sorry. I was referring to this right here. These Cawthorne-Cooksey exercises. What they are, they sound simple, but they are complex. They basically have the patient practice eye motions. So you look up a series of times, you look down a series of time, to the left and the right. You do this over and over again. You follow this with a series of head motions that involve -- especially if one of these motions makes you uncomfortable, honestly. And the therapist takes you through it the first few times.

Audience Question: Can you show us one?

Dr. Harris: I can do my best. Basically with the head exercise, it involves flexing and extending your head and changing the speed that you do that.

Dr. Harris: Any more questions? All right. Well, thank you very much.

Phyllis: Okay. We're getting ready to close down for the morning. I want to thank you all or coming this morning. We had some great speakers. I want to thank Dr. Adunka, and Dr. A, and Dr. Harris. And let us not forget Andrea Crago. She is the reason - she is the reason you are getting all this information.

Andrea: Thanks!

Phyllis: Dr. A will be here for a few minutes after this morning's session before he gets escorted back to the airport. This afternoon will be deaf bingo. Deb Swafford will be leading that, whenever they get back from lunch. It will be here in the conference room. The conference room is going to close at 3:30 to get ready for dinner. It's going to open back up at 5:00. The appetizers will start at 5:30. Make sure you bring your name badges to dinner tonight. And don't forget your -- you have until 10:00 to enter the raffle. So bring those to dinner tonight with you. I think that's all. You guys have been great. Have a great lunch. Come to bingo or go swimming, whatever you want to do. Be back here at 5:00 tonight. Thank you everyone.
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