The newest breakthrough in Cancer surgery

Dr. Quyen Nguyen Transcribed by Jos Roberto Simes Sydney - Australia

I want to talk to you about one of the biggest myth in medicine, and that is the idea that all We need are more medical breakthroughs and then all of our problems will best solved. Our society loves to romanticize the idea of the single, solo inventor who , working late in the lab one night, makes an earthshaking discovery, and voila, overnight everything's changed. That's a very appealing picture; however, it's just not true. in fact, medicine today is a team sport. And in many ways, it always has been. I'd like to share with you a story about how I've experienced this very dramatically in my own work. I'm a surgeon, and We surgeons have always had this special relationship with light. When I make an incision inside a patient's body, it's dark. We need to shine light to see what we're doing. And this is why, traditionally,

surgeries have always started so early in the morning to take a advantage of daylight hours. And if you look at it historical pictures of early operating rooms, they have been on top of buildings. for example, this is the oldest operating room in the Western world,

in London, Where the operating room is actually on the top of the church with the skylight coming in. and then this is a picture one of the most famous hospital in America. this is Mass General in Boston.

and do you know where the operating room is?

here it is on the top of the building

with plenty of windows to let light in. So nowadays in the operating room, We no longer need to use sunlight.

and because We no longer need to use sunlight, We have very specialized lights that are made for the Operating room. We have an opportunity to bring in other kinds of lights lights that can allow us to see what

We currently don't see. And this is what I think is the magic of fluorescence. so let me back up a little bit. When We are in medical school, We learn our anatomy from illustration such as this where everything's color-coded.

nervers are yellow, arteries are red, veins are blue. That's so easybody could become a surgeon, right? However, when We have a real patient on the table, this is the same neck dissection

not so easy to tell the difference between different structures. We heard over the last couple days what an urgent Problem cancer still is in our society. what a pressing need it is for us to not have one person die every minute. Well if cancer can be caught early, enough such that someone can have their cancer taken out, excised with surgery. I don't care if it has this gene or that gene, or if it has this protein or that protein, it's in the jar. it's done, it's out, you're cured of cancer. This is how we excise cancers. We do our best, based open our training and the way the cancer looks and the way it feels and its relationship to other structures and all our experience, We say, you know what, the cancers gone. We've made a good job, weve taken it out. That's what the surgeon is saying in the operating room when the patient's on the table. But then we actually don't know that it's all out. We actually have to take samples from the surgical bed, what's left behind in the patient, and then send those bits to the pathology lab

In the meanwhile, the patient's on the operating room table. The nurses, anesthesiologist, the surgeon, all the assistants are waiting around. and we wait, the pathologist take that sample, freezes it, cuts it, look in the microscope one by one and then calls back into the room. and that may be 20 minutes after per piece. so if your sent three 3 specimens, it's an hour later. and very often they say, " You know what, point A and B are okay, but point C, you still have some residual cancer there. please go cut that piece out". So We go back and do that again, and again.

And this whole process: "Okay you're done. We think the entire tumor is out." We think we've done a good job but very ofter several days later

the pacient gome home we get a phone call: I am sorry once we look at the final pathology, once we looked at the final specimen, We actualy found that there's a couple other spots whee the margins are positive. there's still cancer in your patient." So now you're faced with telling your patient, first of all, that they may need another surgery, or that they need additional therapy such as radiation or chemotherapy. so wouldn't itbe better if we could really tell, if the surgeon could really tell, whether or not there's still cancer on the surgical field? I meam, in many ways that we're doing it, we're still operating in the dark. So in 2004, during my surgical residency. I had the great fortune to meet Dr. Roger Tsien, who went on to win the Nobel Prize for chemistry

in 2008 Roger and his team were working on a way to detect cancer and they had a very clever molecule that they had come up with. The molecule they had developed

had three parts. The main part of it is the blue part,polycation, and it's basically very sticky to every tisssue in your body so imagine that you make a solution full of this sticky material and inject it into the veins of someone who has cancer everything's going to get lit up Nothing will be specific. There's no specificity there. So they added two additional components. the first one is a polyanionic segment which basically acts as no stick backing like the back of a sticker. so when those two are together, the molecule is neutral and the two pieces are then linked by something that can only be cut if you have the right molecular scissors for example, the kind of protease enzymes that tumors make. so here in this situation, if you make a solution full of this threepart molecule along with the dye, which is shown in green, and you inject it into the vain of someone who has cancer, normal tissue can't cut it. the molecule passes through and gets excreted

However, in the presence of the tumor, now here are molecular scissors can break this molecular apart right there at the cleavable site.

And now, boom, the tumor labels itself and it gets fluorescent.

so here's an example of a nerve that has tumor surrounding it Can you tell where the tumor is? I couldn't when I was working on this.

but here it is, it's fluorescent. see, so every single one in the audience can tell where the cancer is. We can tell in the operating room, in the field. at a molecular level, where is the cancer and what the surgeon need to do and how much more work they need to do to cut that out. And the cool thing about fluorescence is that it's not only bright, it actually can shine through tissue. The light that the fluorescence emits can go through tissue. So even if the tumor is not right on the surface, you'll still be able to see it. in this movie, you can see that the tumor is green. ok

There's actually normal muscle on top of it. See that? And I'm peelig that muscle away. But even before I peel that muscle away. you saw that there was a tumor underneath. So that's the beauty of having a tumor that's labeled with fluorescent molecules That you can, not only see the margins right there on a molecular level, but you can see it even if it's not right on the top, even if it's beyond your field of view. And this works for metastatic lymph nodes also. Sentinel lymph node dissection has really changed the way that We manage breast cancer, melanoma. Women used to get really debilitating surgery to excise all of the auxiliary lymph nodes. But when sentinel lymph node came into our treatment protocol, the surgeon basically looks for the single node that is the first draining lymph node of the cancer. and then if that node has cancer, the woman would go on to get the auxillary lymph node dissection so what that mean is if the lymph node did no have cancer. the woman would be saved from having unnecessary surgery But sentinel lymph node, the way that We do it today. is kind of like having a road map just to know where to go So if you're driving on the freeway snd you want to know where's the next gas station, you have a map to tell you that gas station s down the road. it doesn't tell you whether or not the gas station has gas. you have to cut it out, bring it back home cut it up, look inside and say."Oh yes, it does have gas." So that takes more time Patients are still on the operating room table Anesthesiologist, surgeon are waiting around. That takes time. So wit our technology, We can tell right away. You see a lot of little, roundish bumps there. some of these are swollen lymph nodes that look a little larger than others. Who amongst us hasn't had swollen lymph nodes with a cold? That doesn't mean that there's cancer inside. well with our technology. the surgeon is able to tell immediately

which nodes have cancer. I won't go into this very much. but our technology, besides being able to tag tumor and metastatic lymph nodes with fluorescence, we can also use the same smart three-part molecule to tag gadolinium onto the system so you can do this noninvasively. the patient has cancer, you want to know if the lymph nodes have cancer even before you go in. well you can see this on a MRI. So in Surgery. it's important to know what to cut out. But equally important is to preserve things that are important for function. So it's very important to avoid inadvertent injury. And what I'm taking about are nerves. Neverves, if they are injured, can cause paralysis, can cause pain. in the setting of prostate cancer, up to 60 percent of men after prostate cancer surgery may have urinary incontinence and erectile disfunction that's a lot of people to have a lot problems and this is even in so-called nerve-sparing surgery which means that the surgeon is aware of the problem, and they are trying to avoid the nerves. But you know what, these little nerves are so small, in the context of prostate cancer, that they are actually never seen. they are traced just by their known anatomical path along vasculature. And they're known because somebody has decided to study them, which means that we're still learning about where they are. Crazy to think that we're having surgery. we're trying to excise cancer, we don't know the cancer is. we're trying to preserve nerves; we can't see where they are. So I said,wouldn't it be great if could find a way to see nerves with fluorescence? And at first this didn't get a lot of support. People said. " we've been doing it this ways for all these years. What's the problem? We haven't had that many complications"

But I went ahead anyway. And Roger helped me And he brought his whole team with him. So there's that teanwork things again. And We eventually discovered molecules that were specifically labeling nerves. And When we made a solution of this, tagged with the fluorescence and injected in the body of a mouse, their nervers literally glowed.

here you're looking at a sciatic nerve of a mouse, and you can see tht that big, fat portion can see very easily. but in fact, at the tip of that where dissecting now, there's actually very fine arborizations that can't really be seen you see what look like little medusa heads coming out.

we have been able to see nerves for facil expression, for facial movement, for breathing every single nerve nerves for urinary function around the porstate. we've been able to see every single nerve. when we put these two probes together...

so here's a tumor. Do you guys know where the margins of this tumor is?

now you do

what about the nerve that's going into this tumor? that white portion there is easy to see. but what about the part that goes into the tumor? Do you know where it's going?

now you do Basically, we've come up with a ways to stain tissue

and color-code the surgical field. this was a bit of a breakthrough. I think that it'll change the way we do surgery

We published our results in the proceeding of the Naional Academy of Sciences and in Nature Biotechnology. We received commentary in Discover magazine. and the economist. And We shoed it to a lot of my surgical collegues. They said. " wow!" I have pacient who would benefit from this I think that this will result in my surgeries with a better outcome and fewer complications." What need to happen now is further development of our technology along with development of the instrumentation that allows us to see this sort of fluorescence in the operation room. the eventual goal is that we'll get this into patients. However, We've discovered that there's actually no straightforward mechanism to develop a molecule for one-time use. Understandably, the majority of the medical industry is focused on multiple-use drugs, such as long-term daily medications. We are focused on making this technology better. We're focused on adding drugs, adding growth factors

killing nerves that are causing problems and not the surrounding tissue. We know that this can be done and we're committed to doing it. I'd like to leave you with this final thought. Successful innovation is not a single breakthrough. it is not a sprint it s not an event for the solo runner. Successful innovation is a team sport, it's a relay race. it require one team for the breakthrough and another team to get the breakthrough accept and adopted. And this takes the long-term steady courage of day-in-day-out struggle to educate, to persuade and win acceptance. And that is the light that I want to shine on health and medicine today. Thank you very much

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