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Introduction and Disclosures | Applications of Nanotechnology in Interventional Oncology
Introduction and Disclosures | Applications of Nanotechnology in Interventional Oncology
Nanoparticles and History | Applications of Nanotechnology in Interventional Oncology
Nanoparticles and History | Applications of Nanotechnology in Interventional Oncology
chapterdnafull videohelixnanoparticlenanoparticlesnanotechnologysize
Nanomedicine | Applications of Nanotechnology in Interventional Oncology
Nanomedicine | Applications of Nanotechnology in Interventional Oncology
chaptercreatefull videogoldlayerliposomesmedicinenanonanoparticles
Cancer Research and Nanotechnology | Applications of Nanotechnology in Interventional Oncology
Cancer Research and Nanotechnology | Applications of Nanotechnology in Interventional Oncology
apoptosisbloodcancercellschapterdeliverdiabeticdiagnosisfull videogenemetastasizenanoparticlesnanotechnologyreproduceretinopathysignalstumor
Enhanced Permeability and Retention Effect | Applications of Nanotechnology in Interventional Oncology
Enhanced Permeability and Retention Effect | Applications of Nanotechnology in Interventional Oncology
Drug Delivery and Microbubbles - Slow Tumor Growth | Applications of Nanotechnology in Interventional Oncology
Drug Delivery and Microbubbles - Slow Tumor Growth | Applications of Nanotechnology in Interventional Oncology
Pitfalls to Nanotherapeutics | Applications of Nanotechnology in Interventional Oncology
Pitfalls to Nanotherapeutics | Applications of Nanotechnology in Interventional Oncology
Magnetic Localization and Transarterial Chemoembolization - cTACE | Applications of Nanotechnology in Interventional Oncology
Magnetic Localization and Transarterial Chemoembolization - cTACE | Applications of Nanotechnology in Interventional Oncology
Intra - Tumoral Injection and Nanoembolization | Applications of Nanotechnology in Interventional Oncology
Intra - Tumoral Injection and Nanoembolization | Applications of Nanotechnology in Interventional Oncology
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Sorafenib Microspheres - MRI Properties and Histology | Applications of Nanotechnology in Interventional Oncology
Sorafenib Microspheres - MRI Properties and Histology | Applications of Nanotechnology in Interventional Oncology
Electro Nanotherapy - Nanoablation and Photothermal Ablation | Applications of Nanotechnology in Interventional Oncology
Electro Nanotherapy - Nanoablation and Photothermal Ablation | Applications of Nanotechnology in Interventional Oncology

interventional fellowship with the University of Pennsylvania she also has a masters of science and clinical investigation from northwestern university dr. white is currently an associate professor with the Medical College of Wisconsin dr. white

specializes in interventional oncology she currently runs a translational oncology lab that focuses on the selective delivery of nanotechnology-based drug delivery platforms for the treatment of primary

and metastatic liver tumors she began her career and research in a molecular biology lab at the University of Pennsylvania and also spent time with the NIH she has received numerous awards for her research from the organizations

including SAR the association of university radiologists rsna and the cardiovascular and interventional radiologic Society of Europe she was most recently awarded the very prestigious Gary J backer young

investigators award in 2016 I have the privilege of working with this woman every day and being professionally mentored by her so it's particularly special to have her here speaking to you guys today please welcome her to the

podium so just to start I have a bum foot and everyone keeps asking why so it's a stress fracture I just had a baby and apparently when you're pregnant old and I'm carrying that extra weight and wearing let every day you get a stress

fracture of your middle kanana form which it's a stupid bone to fracture so it's not a cool thing that I jumped out of a helicopter and broke my thought it's not cool at all it's just I was bad old and pregnant so just that's why very

typically I will walk around the room as my technologist know and throw candy at you because I have a bum foot I figured that you didn't want to see me fall on my face so no candy today but just imagine i'm giving you candy for

responding to me so we're going to talk about applications of nanotechnology so you all have come into contact with nanotechnology in your lifetime and all sort of go through that what i want to say before i start though is that this

is all cool and up and coming and just what dr. Miss Rose showed you but really the coolest talk I saw in your sessions that I've come to was dr. Waldman came and spoke and back in the day back in the 50s and 60s when he was doing what

he was doing he really paved the way for the rest of us that can do these cool things because without getting a catheter in into a selective artery we would never be up here and so I was just you know

astounded that I could be in the same room with him and and see him talk he actually examined me and Louisville and as part of the examination process they have to ask you questions and you have to interact and so dr. Waldman I walked

in and and he said hi I'm Arthur Altman and I said I know who you are and he said okay let's start and I couldn't talk so he said that's an angiogram Sarah it's an angiogram right I'm like yeah yeah yeah Tik Tok you need to talk

or you're going to fail so anyway I just wanted to tell you that that he's just a really great in the field and its really an honor that you all got to speak with see him these are my disclosures so what

does the nanoparticle nanoparticles are

just a description of a very small entity so so just to put it in perspective imagine me holding a marble and it's a marble to the size of the earth that's how small it is when we think about things one nanometer is a

billionth of a mirror that doesn't mean anything to me that's why i used the marble in that analogy but two nanometers would be the diameter of a DNA helix a very very tiny size that we're talking about so what's the

history of nanoparticles Richard Feynman wrote a book called there's plenty of room at the bottom in 1959 and he sort of imagined a world where we could sort of take atoms and manipulate them and create new things the term

nanotechnology was coined by nereo taniguchi in 1974 and then Eric Drexler wrote this engines of creation book where he where he imagined a world where we could have the entire library of congress on something the size of the

sugar cube and we're there right we have these teeny tiny little microchips in your computer that can have tons of information so we spend about ten

billion dollars annually on nanotechnology and research if you can

imagine that so nanotechnology is not just in the lab it's everywhere I was giving a lecture and they I was at I should say that I was at a national meeting and they're talking about biomimicry and actually the stuff they

spray on your windshield to make the water beat up that's nano technology so it's a part of your everyday life you just don't know it but that's that

that's nanotechnology so nanomedicine is the particular usage of nanotech

nanoparticles in medicine and the reason that we think it fantasia's is it's really the size of of things in nature and things in medicine so you can see red blood cells are in the order of nanometers and antibodies

these are all sort of in that same size range there's nano nano particles come in different flavors to liposomes if you think of a cell it has a by lipid layer membrane layer and that's just what a lysosome is and we can create these in

the lab we can create dendrimers it's basically like roots of a tree where we can grow them out to be different sizes that gold nanoshells is just a particle of gold and the reason we like gold is that you can heat it up in it it makes

things hot and then there's some other types of nanoparticles so it's not just one thing it's just a bunch of different structures that we can develop that are

really teeny tiny so how do we use them in cancer research well you can use them

in a bunch of different ways you can use them in drug screening you can use them to deliver genes i have an example in my lab we're working with an ophthalmologist who is trying to figure out how to treat diabetic retinopathy

and so he's developed a gene vector and if he gives it through through the IV it never makes it to the eye because it gets sequestered out by all the other cells and so what we do is we go up into the artery that supplies the eye and we

deliver this gene locally and it actually helps prevent diabetic retinopathy and so that's just a way of using nanotechnology particles are very tiny we can use it for diagnosis so if if these nanoparticles will hone to

tumor cells we can say yep that's a tumor that's not a tumor we can deliver drugs there an we're going to talk a lot about that because that's what we do particularly in my lab again detection where are these things we can track them

we can say how much drug was delivered and then diagnosis and monitoring so patients coming for follow-up do they have two more don't they have ten where we can use it that way so how does cancer work since I am a cancer doctor

there's a bunch of different things that cells have to be able to do to be cancerous they have to evade apoptosis so those signals that the cells are telling them I you have to die you have to diet has to say I don't care I'm not

going to die you can tell me that but I'm not going to they have to be self-sufficient so they don't have to rely on their surroundings to survive because they have to move they have to go from their site of origin and

metastasize elsewhere they also have to be insensitive to those anti growth signals so when the body says you know it's not time for me to replicate they have to say you know what I don't care i'm going to replicate

they have to be able to invade and metastasize so that's sort of what I voted to earlier and they have to be able to continue to reproduce over and over and over again because what good would a cancer cell be if it couldn't

reproduce itself and then they have to be able to sustain angiogenesis or what that means is that they have to be able to get nutrient and how do they get nutrient they send out signals that say I need blood you need to develop blood

blood vessels so I can continue to grow so this is sort of a six hallmark of what cells have to do to be able to do

when cancer cells grow they don't grow normally I talked about they sort of

send out these signals that say I need to grow I need to grow well they don't grow normally normal cells have time cancer cells don't they want to go quickly and so when they grow they don't have the tight junctions that you would

see in a normal cell ok so it's and we can use that to our benefit by getting by penetrating tumors by giving drugs that way it's called the EPR effect so because they don't have these tight junctions they're sort of leaky we

anticipate that if we inject nanoparticles intravenously those nanoparticles will deposit into the tumors because it's a different different structure than the normal cells there's no gap there's a gap in

tumor cells so the nanoparticles will preferentially go into the tumor and that's called the enhanced permeability and retention affect the EPR effect now

there's a bunch of different types of drug delivery we know that they're

systemic which is what we're all used to so we just injected into the IV and the patient gets all of these systemic side effects right they lose their hair they get nauseous they have all these other issues or we can do passive targeting

which is where we basically injected in a particle and we hope that the EPR effect works these are the clinical trials going on with nanoparticles today you probably don't know it but a lot of the chemo therapeutic agents that we

deliver to patients are nanoparticles they're liposomal components and that's just because we think they are more effective and have less systemic side effects but really in the lab we can do lots of fancy things we can make them

actively targeted to tumor so we can put antibodies on them so they go directly to the tumor we can we can put antibodies on them so they go to the blood vessels and the other thing we can do is trigger drug release so we can

inject them and then we can say you're only going to release your drug where I tell you to release it because I'm going to trigger you to release and I'll show you an example of that so this is triggered triggered drug

release so this is an example of a nanoparticle that's basically a microbubble so all it is is its air with a core and what happens if you insulate it with ultrasound you put also ultrasound on top of the blood vessel on

top of the tissue that you want it will come down and what will happen to the microbubbles is they will expand contract expand contract well they don't particularly care to do that then they explode when they explode they become

nano shards to become these teeny tiny little shards that are small enough to get through that leaky blood vessel the hole right that we talked about with cancer those nano shards will go into the tissue and then they will deposit

their drug if we have coded these micro bubbles with drug so does it work it does and this is pictures from our lab these are the micro bubbles that we created again here on the image be you just see it's it's hollow there's

nothing in it but air and we need that air for the ultrasound image Steve just shows that it's coated with doxorubicin which is red when we look on it under fancy cameras and we like doxorubicin because it is red we don't have to put

some special marker on it and then image d it's just a picture after it's exploded so it's in these teeny tiny pieces it explodes and that's what goes into the tissue and will help kill the tumor these are our ultrasound images of

tumors and you can see the micro bubbles are sort of swarming around we can see them it's an ultrasound contrast agents we can see it the image that says free ducks is just when we infuse doxorubicin directly into the vein so you're not

going to see it because it's not a contrast agent on the bottom it just shows you that you see a means that that's the ultrasound contrast agent it's what we termed it that just means that it's getting to the tumor it's

depositing and the tumor when we take the tumor out there's a lot of drugs it gets in there versus free doxorubicin there is drugs that will get there it's just not as concentrated as if we do it that way so does it work it slows the

tumor growth the blue line shows of the tumors are growing more slowly the purple line shows that the tumors continue to grow more rapidly if they're not triggered and they have it so nanoparticles offer this great site

targeted drug delivery and we're all interventional radiologists so should we all go home or unemployed let's just find a new job well thankfully no right because we talked about sites elective

there's a lot of pitfalls with nano therapeutics there's re s sequestration so think about your reticuloendothelial system so that's your spleen your lymphatic so as soon as they see something that

they don't like or they don't know what it is they take it out of your body so when we infuse nanoparticles through your IV they get sucked out and there's a very low deposition it will actually go to the tumor the other thing is that

there's heterogeneity of the EPR effect so we said I said those cells are not tightly bound but that's not universal you know maybe some of those cells gruesome up in a shorter time frame maybe some of them faster and maybe some

of them have to type Dunstan's maybe some of them don't so it's not really consistent with all tumors the other thing is we i talked about you could put these fancy monoclonal antibodies on them and then it would hone to tumor as

well that's not exactly it doesn't exactly make a big huge difference in getting deposition of these nanoparticles into tumors so how can we

get them there in sort of a creative way you know we're interventional

radiologists and we like to you know pave the way you saw dr. Walton he paves away so this group looked at nanoparticles and they put a magnetic component in it and then they put a magnet over the side of the tumor and

look at that the nanoparticles will actually go to where the tumor is it's fascinating right all you have to do is put a magnet on your belly and now all of a sudden I'm getting treated for cancer and I'm decreasing the amount of

systemic drug that's floating around my body so that's sort of a creative way this is just again nano therapeutics and I are image-guided delivery is how we think we can do it better than just putting a magnet on your belly okay we

don't have to do that we can actually get into those arteries and deliver it locally so you all are very you know adept at conventional team mobilization this is just an image of an HTC and it's the tumor is on a stock and you can

imagine if i have a nanoparticle i could inject it directly into that tumor and have a good effect the other types of things that we do and I are you guys know this thermal ablation this is an image of an ultrasound probe going into

a liver and the image on the screen right is image from my lab this is when we did cryoablation of a tumor and a rat and the reason I show you this is that it when we all do cryoablation we never see it right we just suit sort of this

defect on CT you never could see the ice ball so when I did this for the first time I thought this is the coolest thing at everything's been like oh my god have to see what the ice boat looks like turns out that before I got this I froze

the whole mouth because you have to use mouse settings or not human settings but nonetheless here is a nice bowl after much after much going back and forth

so how do we get its site selectively there well we can just do enter to Merle

injections if we can just inject directly into the tumor we an interventional radiology or leaders and how to you know get something through a needle somewhere and they showed in this study that if you do inject it directly

into the tumor it gets there first of all and second of all it's high concentrations it stays there and sort of all it decreases the growth of the tumor so that's really amazing these images are from actually dr. omaree's

lab and thanks to them for giving me these images but this is essentially nano embolisation where we're doing just what I talked about on that conventional chemo Malaysian slide where we're injecting nanoparticles directly into

the tumor and this is a rabbit liver it allows us to get high concentrations it circumvents that sequestration so they're not going to be sucked out by the spleen or the lymphatics and you can actually see where they're going you can

visualize where they're going the other fancy thing we can do is we can put some iron in it and when we image iron on MRI it changes what color it looks like so tumors look like they're bright so they're sort of whitish that's what's

outlined on by the red and the after picture you can see it turns dark so that's what iron does then we say oh we actually nailed the tumor because the tumor went from white to dark if you have non-target or two or nanoparticles

to go to the liver you'll see the liver double turn Burke as well and so some of the things that happen in humans after we do chemo Malaysian is that angiogenic factors get turned on now this is in human safety test date they drew the

blood and these are angiogenic factors so those are the factors that to tumor says I need more blood supply I need more blood supply and we tested that in humans and it turns out that those angiogenic factors get elevated so is

there a way that we can with nanotechnology get these levels decrease because we don't want those signals turned on we want the cells to be dead we won't don't want them to be saying I need more blood supply how can I get it

was in our lab and she developed the Saracen and microspheres so why is that you know why is that important what does that mean why can't you just give her the drug patients the drug well it turns

out that this drug is very poorly tolerated patients get sloughing of their skin on their hands in their feet so they can't walk but maybe they get the benefit of the drug the other difficulty with this drug is why can't

you just infuse it like we do for key memorization what's lipophilic so it's that right so if you infuse fat it's just going to come out it's not going to go it needs to be so she dances she developed these

very fancy nanoparticles that would go into the bloodstream they wouldn't precipitate out they wouldn't be fat globules and we could inject them into tumors and what we found is you know she put iron on them so that we could see

and this is just images from the MRI showing you that as we go up in concentration the images go from white to black that means we can see them and we know that as the concentration goes up it gets darker and darker and so does

it work so we tested it in vitro so that's just in a petri dish we put it in with a petri dish and does it kill cell so it actually does kill cells which is good what we want and then we delivered it into the into the liver this is just

a tumor before we embolize this is after you see pruning of the vessels and on an MRI you can see again it goes from white the dark now it's not completely dark you're getting that speckled appearance but that means that those nanoparticles

are actually getting to the tumor we do histology so we take it out iron iron turns blue on particularly Prussian blue staining so we know that the iron actually got to the tumor but it didn't look like if you look at that last slide

it didn't look like it penetrated the tumor so that big clump in the center that's the actual tumor but it sort of looks like it went around the tumor so how can we get it into the tumor how can we get it to penetrate more into the

tumor so there's something called a lecture of nano therapy which is essentially using electroporation so if you've ever heard of this you know there's a bunch of people that do electroporation essentially what it is

is your electrocuting the tissue you have to have two probes in and there's a signal that goes from one probe to the other and at electrocute thing if you've ever seen us in real life it's very eye-opening it's shocking because you're

justyou're electrocuting a person so the whole little patient will go like this so they have to give you paralytic so you don't do that in animals we don't give them paralytics and it's very shocking the first time you do it

because the whole animal chicking around on the table and kind of freaks me out but any event what happens is the cells instead of if you do reversible electroporation what will happen is the cells instead of being the membranes

instead of being tight they'll loosen up and they'll actually they'll actually be pores within the membrane if you do it irreversibly the pores open and what happens is the things around it will go in and the cells can explode or those

shrivel up if things go move out of the cell so the cytoplasm depending on which direction and you ph and all these other factors they can either explode the cells will explode of the shrivel up when they'll die and so

that's if we couple that with nano nano technology it actually works and we can get more penetration of drug and nanoparticles into the tumors and this is just an example where we did electroporation followed by a

nanoparticle injection and you can see that it turns from light to dark as we want to see and the tumors okay this is just a color map a different way of looking at the white to dark the other thing we can do is photo thermal

ablation I talk to you about gold nanoparticles so we can essentially inject nano particles that have gold in them as soon as gold sees light we have lasers that we can use you put a laser and it hits the gold and the gold makes

it hot you can increase your ablative

zone and we'll talk about that in a little in right now so applications of nanotechnology so how can we use this for me I'm pretty interested in colorectal cancer it's a third most

common cause of cancer-related mortalities nited states it accounts for about fifty two thousand deaths and that's of the total you know probably 600000 deaths it's about nine percent annual its much higher rate than about

a cellular carcinoma and the reason I have particular interested in this is if you think about your hcc patients you cure them of hcc and they died of cirrhosis if they don't get a liver transplant these folks if you can cure

them they live ok they don't have underlying liver disease it's a real problem and so nineteen percent of patients who actually present with liver metastases at the time of initial diagnosis so twenty percent of patient

that's a lot of patience and of those patients only twenty-five percent of surgical candidates and if you can go to surgery and get receptive happy you're dead at five years so this is pretty deadly and we want to find something

that can actually cure them how do we treat them you know standard chemotherapy we just put an IV in your arm and we expect that chemotherapy will work they've made a lot of advances with monoclonal antibodies they have these

drugs that are bitter attacks just to cancer cells and that has really improved survival over time if you look at the NCCN guidelines these are all the guidelines I'm coming from this is how doc cancer doctors know what to treat

and what drugs to use it says a blade of techniques which is great and also says intra-arterial therapy so they understand cancer doctors understand that we are part of the care and we should be so the clinical need really is

you know let's say they have one isolated metastasis in the liver and this is what i'm showing you example is we can do an ablation an ablation really only works if you're about 4 centimeters ok if it's bigger if

you know let's say they have one isolated metastasis in the liver and this is what i'm showing you example is we can do an ablation an ablation really only works if you're about 4 centimeters ok if it's bigger if

it's on the order of you know five centimeters we're getting bigger we're not going to get a complete ablation and so the other issue is that there's really a risk of damage to the adjacent structures if i turn my power up I can

get a bigger ablation zone but in this picture you can see I'm adjacent to the coal and I'm adjacent to the gallbladder and so I could kill the tumor but now I've got a perfect colon and the patient you know is in the ICU and has to be to

collect me so the purpose of the studies that i'm going to present to you is that we've basically developed a new ablation therapy that would enhance the ablation zone to treat colorectal liver metastases we were going to use the

inherent capacity of gold so that that ability to heat up to increase our

ablation zones and so we went about we wanted to make a nanoparticle so what did we want we wanted to be able to see it and so I've told you before if we put

iron and we can see it on mr we wanted it to be a sensitizer so we put gold on it and then I wanted it to only go to the tumor cells I didn't want it to go everywhere else so i put a monoclonal antibody on the nanoparticle and then it

would go only to the tumor the other thing is we had to have a we had to have an animal model so we developed this colorectal liver metastases cell line it's basically you you give these rats this compound and they develop colon

cancer the colon cancer spreads to liver they took they took those cells out of the liver those cancer cells out of the liver and they grew them and put in a dish and then we can use those cells as our injection into the rats this is just

the antibody we used they had developed this towards this cancer model so we could use it and this is essentially what what our nanoparticles look like if you look under a very high-powered microscope you can see this is just what

they look like they're very very tiny we wanted to make sure that when we heated them they actually got hot so we did that in the petri dish it works they get hot we wanted to make sure we could image them and that's what you see going

white to dark as we increase the concentration we wanted to make sure that we could tell the concentration of iron so you can actually do some fancy mathematics and determine exactly how much of the iron is getting there which

would sort of correspond to how much of the drug would be getting there and then we wanted to make sure that it was targeted who wanted to make sure those monoclonal antibodies are actually going to the tumor and those are just some

fancy images showing you the blue is just the nuclei of the cell the red is my Nana nanoparticles and you can see when you overlap them as the nanoparticles are actually going to the cell nucleus which

is where you want to go these are very fancy images from high-powered microscopes called tem and what you see here is that black cluster of stuff that's the cell has gone and it's eaten up those nanoparticles so now it's

inside the cell so now if i hit a late by shine a laser on this cell it's going to heat up hotter than the cells surrounding it this is just a picture of when that cell is going around and it's going to eat those nanoparticles that's

the black cluster when we put nanoparticles and it didn't have the monoclonal antibodies we didn't see them go inside the cell so we needed two monoclonal antibodies did in fact help here's just another picture showing it's

next to the cells but it's not actually within the cells and then we wanted to make sure that photo ablation actually worked if we put the nanoparticles in the cells lived if we did the nanoparticles with a laser you can see

more cells died so it actually did get heated this is just the in vitro response it just shows that as we inject new particles and do laser we have death of the self and this is how we make the

tumors okay you have to make tumors when

you're doing science and we just x plant deliver you just make a teeny tiny incision UX plant deliver you inject those cells we talked about before you let them grow for a couple of days you monitor by MRI this is just showing that

the tumor is growing and then you can see it going from white to dark sunaina particles are getting there this is just the fancy stuff we talked about before where you have the color map showing a different way to show it goes from light

to dark and then there is a change in the color this is all this map is showing you that this is a change of the color from white to dark these are again we explanted delivers exploit to the tumors you can see this deposition that

blue stuff this deposition of the iron around the tumor which is what we want to see and then we look where did that where did the nanoparticles goat in this case we used ivy we didn't do site selective this is a small animal model

it's hard to get it exactly where he wants we tried a divey to see if it would work it actually did deposit in the tumor but look where it went mostly at re s right they went to the spleen exactly where we thought it was going to

go so we did have some effects from that so then we did photothermal blasian after we infused the nanoparticles we waited and then we put the laser on the tumor and we said okay let's heat it up and let's see if this works and what we

found as you can see the nanoparticle and the monoclonal antibody nanoparticle got the same amount of heat which doesn't really make sense right because I just showed you those images where the cells take up those those nanoparticles

and the other so the nanoparticles that weren't tagged weren't taken up by the cell so why is the temperature the same you'd think it would heat up more if the cells heads gold within them well this camera that

we take pictures with to determine temperature is superficial so it's not going to show you what's happening deep down into the tissue and here is images from our histology and you can see the dotted line shows you just what kind of

burn we get so if we just have a nano particles that don't have the monoclonal antibodies on them so they don't home they just go because of the EPR effect you can see it's just a very superficial burn but if you look at the monoclonal

antibody with tags nanoparticles you get the huge donut ablation it's deep within the tissue so this in fact if we would use this in humans would allow us to get a much deeper penetration without the risk of damaging those surrounding

structures and this just shows you the percent necrosis when we use those different nanoparticles so when I

started this talk I said that nanoparticles are all around us and we see them every day and we don't even

know about them I was going to give a talk about nanoparticles over in Europe and I was in the O'Hare and on the wall they had all these images of nanoparticles as art so not only are we using them in science and and everyday

use they're also art and I think I'll stop there happy to take questions and of course these are all my collaborators and everybody that helps do the work at Fontaine dr. Emerich satisfied [Applause]

are there any questions for dr. white were any of the other presenting I'll tell you dr. over just asked me was that me parachuting no that's not how it broke my foot so that's a picture of a patient and I always put that at the end

of all of my talk so I should have explained that so I had a patient that came in to me and he was given a terminal diagnosis I said you have a to see and you three months to live and you're going to die because he had

metastatic disease on presentation and I saw him because they had put a chest port in and know they were doing a lung biopsy to see if it was a met and while they did we're doing a lung biopsy they they caught in pneumothorax so they

called me and I said can you come run and put a chest tube in and I said sure and then i said what is the biopsy for and they said oh we think it's metastatic HTC i said well what do you mean he has a terminal diagnosis we can

treat this and so we treated him we treated him with seven conventional T mobilizations and he actually lived for three years and his goal was that he wanted to go parachuting with his son when it's done turned 30 and that was

him parachuting with the Sun we turn 30 and so going from a terminal diagnosis of you have three months left to live or not 23 years later parachuting was a son that's why i always put this at the end of talks because i always want to

remember remind myself why we do this not just the fancy technology but it's the save patients life or to let them live longer [Applause] the reference so there there are

actually trials in humans and we've we've phase 1 phase 2 trials there's a lot of stuff being done by the ablation ests because they think that this nanotechnology can increase ablative capability so there's doxorubicin that

has sort of been utilized what's that now that's it yeah so that we have these these nano particle like doxorubicin structures that they've been using to see if they can increase ablative technologies there's a lot of stuff in

the breast that they're using nanotech nanoparticles for so it is in human trials that that slide I gave you with all that that list those are all human trials clinical trials going on at Santo technology so it's out there it's being

used a lot of the gold stuff that I talked about is actually not you know FDA approved for certain uses and can be used for ablation

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