Bile Duct Cancer Symptoms

>> good afternoon. we're going to get started and let those who come in late, join us. at the conclusion of any presentations, we welcome ask questions, even during them so it's not so formal but i would request that we wait until we

get a microphone to you because every week there are between 2 and 400 people at nih who are watching this live and they send me e-mails saying we heard the answer but we don't know what the question was. so it makes it a little bit clearer.

2 or throw days after all that, these programs go out on the nih video archive where they go around the world and they're replicated now in 18 countries and over 2 dozen major north american institutions. so there's quite an audience out there and they'd like to hear

your questions. so some of you i think haven't been here before so i'll begin with a quiz. what is that? you know. what is it? and yeah, actually taken by my grandfather believe it or not

and that weigh been on the other side in the 1860s so you know we show this because the purpose of this course is to put us in the same position as these gentleman who are on the cat walk. felt in fact, women used to pose on this thing with their billowing skirts and the wind

blowing it was a very fashionable thing to do. i think 1 or 2 of them got blown overboard. so the point is we're trying to link exciting advances and challenges and basic biological and physical sciences with major health problems.

and so the whole purpose of this course is to convert everybody into a bridge builder, an engineer. think out of your box. for those who have clinical experience, the speakers provide some of the state-of-the-art of the thinking of what the

problems are and what we really don't tell or should know. and if you've had little or no clinical type of training or experience, the intent is to give you a sense of why these diseases that are discussed are important. all of this is on the web site

and you can download power points for the past pest years in you wish that cover an, normous range of materials. so today, unfortunately, snorri thorgeirsson, who is a senior scientist globally known for his work in this field is ill with the flu.

and so, i'm going to do a very substitute a little bit because i don't think anybody can fully substitute for snorri. but i will take you through parts of the cancer cell lit array story and problem. we hope at the end of which you will have a pretty clear as to

why there's so much interest in this what the challenges are. so the upper panel there is what the normal liver looks like when it's stained for the traditional stain and i won't go into the anatomy but you get a gesctalt, that looks like the hepatocytes. so these cells only divide once

a year. so can you spend years looking at normal liver in micro scopic section that you're rarely if ever see a mitotic figure. the thing in the middle is what it looks like when the liver loses its symmetry and everything, it becomes a mass of

scar tissue and regenrative nodules and altered circulation and that's cirrhosis. and that causes cirrhosis, and cirrhosis is a factor but it's not the only 1 in primary liver cancer. we'll get to that. down at the bottom there a

histology of what it looks like when it's abnormal with inflammation and vasculature and funny looking cells with mitotic figures. now--now, okay. so i want to say a word about this. it may be surprising to you but

not so many, many years ago, maybe to you it seems like many years, to me it seems like yesterday, but definitely in the 70s, that isn't too far back, if you visited in the orient, japan, china, or sub-saharan africa, primary liver cell cancer was the number 1 disease

for hospitals and i remember visiting a hospitals in shanghai, about 90% of the people there had primary liver nobody got too excited about it. unfortunately the patients all died, it wasn't unusual but there were primary liver cancer patient that appeared in an

american, north american hospital, that would be presented at grand rounds. because our hospitals were filled with people dying of cardio vascular disease, corownary heart disease which at that time was very rare in the orient and subsan francisco hair

an africa. let so this is a dramatic business and nobody paid too much attention in this country to primary liver cancer because it was, you know a rarity and there were so many other things to do. we were not deeply involved in

global medicine in the 70s or in the 80s. but now it's the fifth most common cancer in the united states and it's it is second most lethal 1 world wide. and it's increasing at a rate much greater than the rate of increase of any serious cancer.

i mean i'm excluding some of the more manageable skin cancers and so forth. so this has become a huge problem and we'll so you a bit more, so 1 interesting question is how did that happen? it's not all due to the fact that many people, both people

and others immigrated to the united states but the orient for example. that was an important consideration and for a while we saw patients with liver cancer, they're almost all orientable, and they were in their 50s, so forth.

and that was the picture. dramatically changed. that does exist now. but there are many other clinical phenotypes, so it's not just that individual that 1 looks for clinically for this disease. and why is it so lethal?

now, you all know where the liver is. can you all put your finger on it. it's the size of a football. you're on the wrong side, sir, it's on the right upper left. so it's like a football under your right rib.

so the interesting thing is is it didn't have any serves except on the sensory capsule which is 1 lay they're surrounds the liver and the only pain you ever get from the liver is when something effects that capsule. so you have this big solid organ in the body, the size of a

football and a lot can go on there and you wouldn't have a clue. that's 1 of the factors that involves that's lethality because the struggle is to diagnose it before there are any symptoms here. by the time there are symptoms

what it means usually is that the tumor has invaded something, the blood vessel, about bile duct, it's done something and it produces a whole variety of rather serious clinical problems that may be bleeding there may be jaundice and all that, by that time, you know it's too

late. so that's 1 of the reasons for the lethality. now it's double in the united states over the past 2 decades and we'll show you 1 graph here to indicate that the predictions are, this is going to continue. i hope at this point you're

thinking why? we'll get to that at least. what we think we know is the why. now the other interesting thing is, that this cancer has a characteristic of being drug resistant. now many cancers particularly

leukemias and so forth that become drug resistant when people are given drugs. but the liver is frequently resisted each if smoke was treated with an anticancer drug. we don't fully understand that, except for the fact that the liver is the main place where

all the garbage of what we eat and what our bugs do in the intestine travels up through the portal vein and it has to go through ted liver. and you may recall that many of the anticancer drugs are natural products who are derived from them so they come from fruits

and vegetables and we don't usually chew the bark off trees but some people do and at any rate, the liver is set up to become drug resistant almost from scratch and that's an enormous clinical problem in trying to devise chemo therapy to treat the liver.

and so the treatment of choice, at the moment at least, the 1s, people who survive are 1s who have surgery. now, surgery. i already pointed out, that if you have symptoms, have you problems because it soucly means that it's pretty extensive.

so it's not terribly surprising that most surgery at least partial reception of the liver is ultimately not very successful but we'll hear much more of this [indiscernible]. but generally speaking less than 40% of people are even eligible for that kind of surgery because

there are multiple metastasis, or it's in a very strategic place and many patients now have total liver transplantation which is somewhat more successful, particularly if it's found early and that's the real problem. felt and that's early, we don't

have a marker that actually says and the set up for doing diagnostic screening and people at risk, you know it's expensive and it's not readily available and it's not so overwhelming successful either. relapses occurs in most patients after cancer because this tumor

tends to spread among bloods vessels for the most part and there there may be multiple sites within the liver or often maybe just a millimeter or less so there are things about the spread about the metastasis that we don't understand either that are challenging.

yeah? >> [indiscernible] >> i think we will hold that and let tim comment. >> [indiscernible]. >> just hold the question for a little while because tim will discuss this in more detail. so for all these reasons this is

a major health problem. this is just a graph to show that the long-term mortality trends up at the top, liver and intra pattic bile ducts, that leads the pack in terms of the percentage increase. there are more and more patients every year, greater percentage

of likewise melanoma, pancreas and so forth, whereas the 1s in blue, it doesn't mean that they are being cured, but means that various things have been done with all of them that toned reduce the frequency, say control of tobacco and it's effect lung cancer and so forth.

so i just want to talk about this 1 a little bit here because i'm going to talk about the upper part of this and then we're going to focus more on the lower part. so i told you about clinical aspects, the tumor may be small, even get to be fairly big before

it does anything and the other thing you should know is that practically ever function of the liver, which includes metabolism, detoxification, secretion, all that sort of stuff, is present with a huge functional reserve. simply putting it there's at

least about 10 times as much functional reserve as we actually use. now that means you have to destroy a lot of liver cell function in order to see that in some measurable metabolic way. let let's say the serum, albumin or co agessulation proteins, so

all of these things contribute to the clinical difficulty. we will hear more about tumor staging and metastasis. now, the setting for primary liver cancer more often than not is on the basis of chronic liver usually cirrhosis, but not necessarily.

now cirrhosis is a situation where liver cells have been damaged and they're stimulated to regenerate but they're regenerating in an organ that is disruptive matrix and blood vessels and everything. so that you get these nodules formed and they seem to be the

set up for the development of we'll hear more about that. now a little bit about demography. for the most part, these are patients, tend to be more male than female but these are people that are in their 50s, 60s, sometimes 40s but there is some

dramatic exceptions. so i'm going to tell you quickly a story of a dramatic exception. the coal mines in south africa are from a mile to a mile and a half below the surface of the earth. they exist at multiple levels with like spokes going out and

in those spokes, people work lying on their backs with pneumatic hammers drilling holes because the gold there is not big chunks that you can just see and grab. they have to extract it from the ore. way back, you could see it.

if you have ever been to south africa, the white water means they saw stuff glistening in the water and that was actually a gold area, but that area has dipped down now geologically, it's about a mile down. so to work down there, you have to be young and very strong and

very well nourished. in fact, it's so hot down there, you have to take about 4000- calories a day. now who does that? in the day when is i went there, these were young men from sim zimbabwe, young, strong, perfectly healthy.

4000-calories a day and they were climbattized to work under these conditions, very hard, very difficult work, okay? and then the classic story was that a young man of about 20, maybe he was washing or shaving 1 morning and he felt something funny in his side and he's dead

within a matter of 4 on 6 weeks of primary cancer of the liver. now in many of those patients it actually happened that fast. how could that be. amongst that population, that was more common believe it or not than life threatening accidents in some of those

mines. so this was big time. well, people look to the environment and in zimbabwe, like in sub-saharan and africa, there's amp low toxin which is a fungal product present in grain and all and so people, you know eat this and amp o toxin in

animals is a good way to make liver cancer, there was a group here that showed that there was a site specific phosphorylation on p53 and that was a flash point for indicating, well it turns out that was due to aflotoxin but that wasn't the whole story because in the

beginning of the 70s hepatitis b virus was identified and if you took the map of where these primary liver cancer was most common, you could super impose where there were high carrier rates for epititis b virus, a double stranded dna virus discovered here at the nih by

barry lumberg and harvey alter who spoke in the course earlier. barry won the nobel prize for it, it was the first hepatitis virus ever really identified and it turned out that people were carriers. and the miners were also where did they get it from?

19, 20 years old. they got it from their mothers. so it was transmitted from birth, and they were never really sick from it, in fact they were living, they looked great. but they had it for 20 years and the tumor developed and they did

not have cirrhosis. some of them did, most of them didn't, so that's 1 picture, okay of what the environment was. so once hepatitis b was recognized and vac nation took place, this was the first cancer to ever be prevented by vac

nation. in taiwan where the risk of primary liver cancer was 400 focused on 1, if you were--400 to 1 if you were hepatitis b positive, the risk of revealing lung cancer if you smoke to packs of cigarettes a day, is maybe only 4 to 1.

so the risk of liver cancer was 10 times greater if you were hepatitis b, well, they instituted a taiwan wide vac nation program because the vaccine turned out to be the surface antigen which is what was originally was detected here at nih, the so called australia

antigen. turned out to be a potent vaccine and is the basis of the vaccines we have now. now you know everybody should get, i hope you all are vaccinated against hepatitis b. so once that happened in taiwan within a short period of time 4

or 5 or 6 years, the prequency of primary liver cancer went like that and it's very, very low, because i think virtually everyone who's vaccinated, it's a disease that's disappeared but it hasn't disappear indeed many of the people who come to the united states from cambodia.

let from laos, from thailand and other places. so 1 of the reasons for the hcc, liver cancer development is we still have the hepatitis b the vaccine doesn't do anything if you're already infected and so forth, so those people are treated with drugs which have

ups and downs and are not as effective as the drugs which seem to, for example, eradicate hepatitis c. so the second thing of importance, if you took the hepatitis b global map, okay, it overlapped the liver cancer map and so it was plum berg and

those people who said ghee, maybe these guys are related to 1 another and that started the whole business of identifying hepatitis b as a major factor. in the development of cancer and it's the factor in the zimbabwe, miners but now it's been replaced by hepatitis c and most

of the cases that are seen now in this country of oriental nature, the majority of them are hepatitis c patients. but as you know, we have drugs which seem to eradicate hepatitis c and i guess perhaps not fully known, documented, but they prevent the development of

but it's interesting that liver cancer is the first cancer that was ever prevented by a vac nation and prevented by a drug employing but then there were a lot of chemical carcinogens, barra sights, micro biota and so forth and so on and there are lifestyle factors that

statistically, you know have a risk that's connected with it, but, i don't think anyone's shown that they're etiologically related. the alcohol is interesting of course because if it's association with chronic liver i don't know whether somebody

who just drinks up on a weekend and gets smashed, that but doesn't have serious liver disease, i don't know whether they're at increased risk. so i just want to tell you 1 other story which i think is irrelevant to all of this. s and that is you have to think

out of the box. so the people who did the hepatitis b work were great thinkers outs of the box, believe me. none of them were liver doctors. okay, blumberg, barry was a rheumatologyst and and an anthropologist and harvey was

a hematologist at the blood bank. he's largely responsible for cleaning up the brood bank of all hepatitis viruses and an amazing accomplishment. used to be if if you have a blood transfusion, at the risk of getting hepatitis was very

high. maybe up to 40%. depending on how many transfusions we have: so, where was i going? ah yes, so think out of the box. so the blumberg people were sitting around and fox chase cancer center and saying, where

does hepatitis b come from? and this is i true 74 74 store--true story. and someone said it has to come from an animal vector. and so someone said where do we get the animals. and to the zoo. so they went to the zoo and got

blood samples from every patient in the zoo hospital and they measured hepatitis b virus, dna virus and polymerization and of all the animals there, 1 of them turned outed to be positive and have dna polymerase in it and that was a wood chuck. so they went ahead and

identified the virus of the wood chuck which turns out to be a family of this hepatitis b. it's not the same and there are several other animal viruses which are of the same family. and the story was that the molecular biologist who did this work herb mill man presented it

and the man in this the back of the room said where did you get the wood chucks. and he said from the zoo. and he said well they're my wood chucks i've been studying them for 10 years and i've been studying them because they develop primary cancer of the

liver. that's interesting. the molecular virologist, they didn't care about the wood chucks and the wood chuck pathologist who was studying the cancer, he found out about this fortumor spectrumitously because he heard their presentation.

the bottom line of the story is that you can infect the wood chucks with the hepatitis virus and they develop an acute inflammation and then they develop liver cancer. the humans don't do that. this is not an acute inflammatory pain either with

hepatitis b or c or any other toxin. it's a whole different business. so now you're ready to think genomicly, informaticly, immunologically, what's going on that can cause these different sort of phenotypes and i'm going to skip that.

because tim is going to talk about this. i would just point out that and we will get back to this in more detail. the point i've been frying to make and it begins on the left over there, the normal liver can develop a tumor going up to the

right which doesn't have anything to do with an underlying chronic liver that's pretty rare but it does happen. and more recently, the past, i think it's 3 years, 2 and half years ago now, it was a established as a form called fib

row lo melar liver cancer which is a liver cancer lethal of young people and that turns outs to be a mutation pka and the pathway of that was elegantly worked out and described and i put it on the web site. we could look it up and the stoma which is the different

kind of a tumor, sort of an earlier form, that also had some molecular type of genomic studies that have been done to indicate. then have you the 1 in the middle where there's a relationship to fibrosis cirrhosis, fatty liver disease,

chronic liver disease, and there, there's a whole raft of molecular abnormalities that have been found and the problem is, what do you do with it. how do you fit it in, to produce it under certain conditions and then, at the bottom, is malignant trance formation and

with the adenomas, so it's transformation which is in the middle that is life threatening and there is recognition. so i tried to point out something about the rather exciding history of this disease and it is because they're huge efforts championship a problem

for this is to diagnose them. how do you survey a patient who say has treated hepatitis c with liver disease, but what do you do to find out, if you do find out what can you do about it. and all of this in the post genomic era, where we're learning more and more about

pathways and mechanisms and that's targets for drugs so that's where we are and so we will learn a great deal, so now we're going to learn a great deal from tim. ful so tim is a position who received his degree in germany and he interned in munich and

did a post doc at hopkins where he began to work in tumor immunology and then returned to germany where he returned in medicine, medical oncology, gastroenterology, became an associate professor and in february of 2010 everybody was very happy when he came to the

in, ih and heads the medical oncology branch of the gi malignancy section. he's the head of it and he's a tenured investigator. so we put up a bunch of tim's publications, that you can browse and now he's going to solve all these problems that i

have enum rate said. --enumerated. [ applause ] >> all right, so thank you very much for the opportunity to present. it will be a bit of a challenge because i am actually 2 people. so i will mention a little bit

about snorri's work but i'm definitely not an expert as much. i will skip parts of the introduction because you obviously heard about this data indicating that hcc is a major health problem, it was the second most common cause of

cancer related deaths and there's only a million of mutators world wide, approximately 35,000 new cases per year in the united states in the data. now before we go to the research what i'm going to do is--i have something here.

so before we go to hcc research, the first thing i would like to do is i will give you a bit of an introduction about hcc from a clinical point of view and tell you actually why hcc is so different than anyone else you've heard in medical oncology.

so let's start with the hcc or start with the liver. now you already know now where you can find it in the body. the interesting thing for me is actually, you know the liver organ is very different than many other organ asks that's significant impact also on the

pathophysiology and treatment. now for reasons which maybe, you can better understand to explain. the ancient greeks new already that the liver is the only internal organ that regenerates. you notice what you can see here on this picture where the eagle

comes and pick on the liver, and the person doesn't die. he comes back the next day and he picks on the liver again and the liver regenerates now i just don't understand how it was--how it was possible that so many years ago people already anyhow that the apparently the liver

and indeed it is the case is the only organ regenerates. so you may have heard that you know, they're going to talk about the transplantation but just, you know different ways of transplantation, and there's actually transplantations where mothers and fathers for the

meta--piece of a liver to a new born which may have some genetic defects that requires immediate liver transplantation, but the amazing thing is you can can don't this because the liver regenerates. so you know it's really the only organ.

it's typical information used cancer so we know about the pathophysiology from a clinical point of view, with the patients first developing hepatitis, liver cirrhosis and then hcc. now the next that is different from an anatomical view is when we talk about treatment.

usually we have an artery that feeds the organ and the vain that takes the blood away. now in the liver, it's a bit different because the majority of the blood supply into the liver actually comes to the portal vein and only 20% of the brood supply comes through the

hepatic artery which is important once we talk about treatment and diagnostic procedure. it's a complex disease because it dears in 80% of the cases in an underlying disease organ. so about 80% of the patients have already liver cirrhosis.

so in other words when we treat the organ or the tumor we also keep this mind key keep the organ in intact and the dysfunction itself can cause many, many problems. as can you see here, so if we forget the cancer for a second, there is many things

hypertension variances that can blood, there is hyper metabolism, this is something called the hepato renal syndrome, there are lot of clinical issues that we have to take care of with patients with orbed lying cirrhosis. it's important to remember

because liver cirrhosis is actually an end stage disease. you can see here, the natural prognosis for patients with severe liver cirrhosis, and in this case, we don't talk about cancer, and you can see on the picketed upure of the patients what we call concentrated

cirrhosis, you can complete as much only with the liver transplant, they have a very short surverifial or outcome as you can see. and obviously this is important to remember because if these patients develop a cancer, the cancer is actually pretty

irrelevant because the underlying disease is actually the life threaten to give in these cases and you better don't start treating the cancer because you can just make the cirrhosis worse. >> so the compensated cirrhosis, so the question was: because

there's no--what is the prognosis of the compensated cirrhosis, it's 75%. these are actually, you know you can treat them with a few drugs to maintain the liver but they are easily treatable without many major issues. and you would definitely not

transplant for instance in these cases and i will will talk about this in a second, these patients have the risk of developing an hcc, so this is the patient population that we would screen and again this is 1 of the main differences from the other tumors, we actually had--we can

identify a patient population which are 4 the high risk developing for tumors. depending on the underlying liver disease, there's a risk of 3-7 or 8% per year to develop an hcc. so obviously this is a prime patient population for screening

and surveillance. now so we--this basically brings us already to the risk factors and to understand these risk factors so you heard a bit about the hepatitis b as 1 of the risk factors and obviously i will show you data about the vac but, the treatment of the

hepatitis itself is actually relevant. what you can see on this study, this is a study that was done in patients with hepatitis b, as an agent study, and mainly what you can see here is if you review the dna viral load in the blood. so this is basically what you do

if you treat a patient with hepatitis c, you can check the blood and you can see how active is the disease and 1 read out is a viral load, if you review the viral load which you can see on the left side, you recuse the incidence of hcc, the same thing on the right if you don't look

at the reduction of the viral load but if you look at the aminotransferase, if you trite the hepatitis you can reduce the risk. now alcohol which has always been a very interesting topic and was mentioned before, so it's unclear how the alcohol

really-of what the risk of the alcohol itself is. the problem is many people have underlying or second factor if you can see on this slide. so you see social alcohol intake which is defined as no more than 2 alcoholic drinks daily or 3 to 6 weeks or get completely

trashedot weekend is actually a smaller number. it can be very significant for patients who have chronic hepatitis c as you can see or for instance in those patients having underlying epititis mesh as can you see on the right side.

diabetes is another risk factor, we have patients that have underlying liver disease are more likely to develop hcc in the context of diabetes. and finally, the interesting health fair or health problem in the western world are visited, there is a very strong

association between body mass index of greater than 35 and the risk of dying from a specific disease as can you see again on this slide. that liver cancer clearly sticks out and i will tell you a little bit about this towards the end of the presentation.

i think this is very easy if you try to understand the mechanism. the liver from a part from how i told you different a part from any other organs is also different because it's the only internal organ that's stores fat. no other organ stores fat.

you won't get a fatty lung or colon, you get fat tissue, but you don't get accumulation of that's 1 of the reasons why the liver is so much at risk in the context of [indiscernible]. so just to summarizeis b, c, many other conditions, hear h bv, hcv, and other factors.

there are numbers that this is going up in the next 5-10 years which is shown here. now this is already mentioned, obviously the hepatitis e titis b vaccine has been very, very successful. it's been reported in taiwan that this is connection to be

used to prevent tumor development. now i told you that patients with liver cirrhosis or under lying liver disease and compensated function have risk to develop an htc. so that's basically suggests that you should do--you should

do some type of surveillance, sometimes of the screening to prevent or to early detect these tumors. from a scientific point of view, it's not that easy to prove this because you know it actually requires quite a significant number of patients to do this.

now there's 1 study and i will will show this because i think it's interesting approach and it has obviously some significant short comings but i'm going to show this to you. so this is a study which looked at the effect of the biannual screening and in this case, it's

basically an isosound and measuring of [indiscernible] in the blood and the study was conduct indeed china. so as you can see, they included the patients with chronic hepatitis b infections at the age between 35-59. they included 19,200

individuals. so it's a huge study, they were randomized to the screening group. and the clinic agreed to participate and you can see, they were followed up and some of these patients developed the problem is the control group

of 9400 individuals was not told that they were in the control in the control, it was a study group on the conducting here, so it's a pretty strongend point here, and if you look at this overtime, you can see that screening is communicated in the ultrasound and every 6 months

can reduce the risk of dying on the hcc. how do we diagnose the hcc? it's difficult when we start talking about molecular diagnostic, et cetera and i was going to go and the details on this diagram but i want to tell you something and this is

something that makes the hcc different from other types of tumors. if you had math o isostudies of multiple endocrines in the liver you can actually just by and i will show you pictures just by doing dynamic imaging, mri or ct jan scans, make the diagnose i

guess of an htc without even getting the biopsy. so you can see here patient patients for instance with a 1-2-centimeter lesion, has 2 different imaging techniques, they are specific for hcc, they have the radiologic hallmarks, and you can see the diagnosis of

the hcc without the biopsy. which is a big deal for everybody that likes to do genomics research and studies that we talk about because these patients never actually undergo biopsy. now you could argue maybe we should do this and i'm--i think

this is something that obviously would be very helpful there're others that say they don't like to biopsy, you can have need will track metastasis and within the this and there is marked with small error, and with the section that was biopsy taken and you can see with the

larger--with the larger in the metastasis and i should say this is a very, very rare event but you cannot exclude it. so this is-- >> so obviously this is the technique, can you use the needles, you can use needles. and go ahead and use control

parts so that you basically cover the needle. you can burn the track so there's a whole old story behind it and i think the risk in theory, in reality right now is actually pretty, pretty low. but i just want to, you know bring this up because it's an

issue if you come from the research point of view and you do these studies and you think now, i get patient population and they all being biopsies and you realize all of a sudden, you only saw the tumor when we start chemo therapy but we don't necessarily require a biopsy.

now the next thing is, for also a few clinical oncologys you probably heard--so when we put the tumors in stage, always note the size of the tumor and then the lymphnodes through the metastasis, or not. this doesn't help with hec, the visitation of tumor stage

suggest different because we actually have to take into account the liver count. these are multiple tumors but they have advance liver function, they die from liver function, that the stages systems, i won't show you this is how they all work, but what

you can see is on the left side, they actually not only include the tumor burden but include liver function, et cetera which is very different and make its difficult to understand how we treat patients from the outside. now this is--this is a summary basically of the treatment gid

lineups as well as staging i'm going to show you here just to give you an overview of how we treat patients with hec,ot left-hand side, you would see the patient it is approximately 30% that undergo purative treatment. these patients have a good

survival rate. can you see it's up to 70% depending on obviously how advanced the disease is, where the patientsot right hand side, receive the treatment. these are patients that are immediate and advanced disease, obviously depending on the

disease, the outcome here is much worse. you can see we do not only look at the number and size of tumors but liver function which is defined by the classification. if you look at ted studies if it is new england prime journal. this is the journal, but it

doesn't work this way anymore. in 1996 this was still possible when [indiscernible] was a surgeon in milan, he reported the--his--the outcome of patients and this is co transactivator point which makes hcc, different than other cancers and usually we don't do

solid organ tran plant but this was an option. but he showed you could do transplant in these patients and you could have a good outcome and this is what we call the elancriteria. as you can imagine, there were other surgeons in other sites

and they were not happy when they heard everybody had to follow the milancriteria, so here you can see pretty much any other side that came up later and depending on the side where the surgeons were working they develop different criteria and then there was somebody that

looked at these different criteria over time and basically what the slide showed to you is that depending on your criteria which are defined as how many nodules the patient may actually have, that you--that under goes transplantation or how large the tumors may be.

you have a different outcome. obviously if you have more patient who is have more or larger outcomes, they have more outcome than if you're restrictive and just include patients with small tumors or very few nodules such as what they did in milan.

now what is better, what is worse and the advantage of the liver transplantation is that you also treat the underlying liver disease, and you take out the organ that had cirrhosis and can protect thereby the development of future hcc where it's the other advantage of

the--for only any lifetime in the suppression. to make things more complicated. alternatively to surgery, you can also optical images intervention or radiologyst to take sophisticated devices you can see here that they put under imaging guidance into the tumors

and then ablat or destroy these tumors indication that's the outcome of those studies are actually very similar for surgeries, so this is something that's individually discussed in patients. >> the radial placement actually performed curative attempt.

>> that's the next slide. so the next part shows you different treatment that we offer patients with a curative event. so either the resection andlet liver transplantations or the ablation as can you see here, typical example, small single

adhesion in the liver and then depending on pullet pel factors you can decide which is the best treatment option for every individual patient. now if patients are--if you can't--if you cannot removal the tumors because they're too large or too many, that's when we call

these patients at an intermediate stage, you can see the result here so for instance in this case, and this patient has at least 3 lesions in the liver which may be difficult to see on the left side, but on the right side, if you actually look at the are--administrative

torior ground where the radiologist have other reads, can you see the again that these-that these tumors are highly vascularized it looks like dark trees can you see and this goes back to the picture i showed here when i said that the liver gets most of its blood

supply through the quarter vain where the tumor vs a different architect and you are they get the supply through the hepatic artery and we use this for the treatments. because if you deploy the chemo therapy into the hepatic artery and we selectively kill those

yes. >> i'm looking at the image and i'm having difficulty visualizing how on do you get to the feeding artery. how do you get to it? that looks like a bill challenge. >> they find small pf--for them

this is easy to--for the different areas. and then finally patients with advance disease, these are patient who is do any of these sophisticated treatments, these patients with such metastasis shown here. these are patients where we

perform chemo therapy and i will briefry summarize here, the data so basically on the left-hand side, the patients where we have curative treatments, different surgical options and ablation, intermediate patients and then the serot nib, and those patients on that have advanced

liver functions are treated with the supported care, we don't do too specific treatment. --with advance liver cancer. >> okay, so that's coming here. so that is basically the result from a study that was conducted or that was published in 2008, and where sorafenib, that was in

large phase 3 study patients and histologically proven hec were enrolled and have liver function and received rapped order of micronsized placebo controlled study and they were randomized to receive placebo or sorafenib, in 2005 to 2006. and you can see here that the

patients were rapped automatickized 299 received sorafenib, 303 received placebo. and so much in favor of the sorafenib, so much was open as an earlier time point, they already noticed that patients actually did benefit and now is to answer your question, so the

outcome stles an increeing in the survivor to 9 to 10.7 months. and now obviously it's up to everybody to decide how much forward progress was this. and this is where we were at. this is the only chemo therapy we have for this type of

and obviously there is--there is a huge unmet clinical needs based on this data. the other point that i just want to briefly make before i start talking about the scientists that obviously the time, the increase in survival is not the only thing.

the treatment is associate wide significant toxicities and put skin reaction and something that we can see here some picture on blisters of patients developed upon treatment and then also other skin reactions here on this side. so obviously it's a huge unmet

clinical need and now the question is what do you want to do and how do you want to develop better treatment? so you see this picture and i'm going to just briefly summarize what snorri's group is doing and what their approach is basically.

obviously what they're doing is they're basically starting to the tumor biology and the tumor genomics in this hcc with 2 different aims. one aim is to really identify subgroups that may be at higher risk or lower risk to develop tumors and then also to have a

set of or worse outcome so that you know we would--that will help us identify these patients and the second and obviously more important and more velvaunt question is, can we find potential pathway to identify pathways that can be targeted using molecular targeted drug

specifically treat patients with so you've seen this slide which is just summarizing some of the pathogenesis of human liver cancer, again, hcc is a little bit complicated because we see in a--we see a--regenrative nodules and as i said before, sirose and i guess prior to

developing tumors and they would finally be better and actually there was a question earlier reguarding the surgery and transplantation of resilience carding recurrence, things are actually more complicated in the resection because if you resect a patient's tumor the sirottic

liver remains in the patient. so if you ask me whether the patient had, if you relapse the chance of relapse is actually high in the first 1-3 years. but then the chance drops but the risk of developing a de novo hcc is increasing so there's 2 different risks that the patient

has to deal with, it's not only the relapse of the primary tumor but because you keep the underlying sirottic liver but you have the de novo hcc at a later time point. now there's different categories and i will not go into those details that we will focus not

only on hepatocellular carcinoma, but we do know there is a number of somatic mutations you can see here in hcc, it's not 1 of the very high--the highest 1s but we do find these and these mutations has been further characterized so you can see here significant chance of

driver gene, driver genes are those genes we hope to find mutated and target because the whyed is to inject the drive of the tumor and we can block or inhibit these genes, we can use them as a treatment target. now i can tell you, so a part from obviously you see here from

the p53 are very treatment changes that you find both in hepatitis b, associated in the different subgroup that has been studied here. the problem that--the read we have noticed in the past years, is that a patient not showing you some of those piblghtures

where patients actually have like 3 or 4 [indiscernible]. the different lesions are actually different in the genetic in the genetic identity. but you may find mewitations in 1 but not in the other tumor and that makes the treatment with the specific target rather

complicated because you may find p53 mutation in 1 lesion but not in another lesion and if you had a good drug that would actually work, you may not end up with the success because it only helps you treating 1 lesion but not the other. now, summarizing that has been

pioneering and understanding the biology, the development of hccbut also identifying gene expression signatures but this is 1 of the slides where it summarizes data and you take samples from patients that have been diagnosed with hcc, performed molecular analysis,

and you identify clusters. you have the clinical outcome of these patients and you can identify thereby patients that have a better outcome or awards outcome and you need to--once have you this data, you basically need to confirm this population, you can see the data

is initially generated in chinese patient and then what's also prone to be true in the western patient population. there's another signature here that can you see using again gene expressions anal sills and you can see what's identify helps you to identify patients

with a better survival or recurring. there's a number of activatingonch o genic pathways, voxly these are the pathways we want to target. you see here, egf r myk, nf cappa b which are the target we try to identify that are

discussed at poetic tential pathways and maybe last but not least, to make this story a bit more complicated in the liver, the idea of the stem cell and this group has identified stem like phenotype which is found in hccs and again different subgroups, which are

characterized by more aggressive growth or more benign phenotypes. the bottom line--the bottom line now coming from a clinical point of view is this. so i've shown you the data of the sharp study which was done in 2005, 2006 published in 2008.

and generated big hype and hope that we would get advance said in the hcc but as it turned out this was not the case. so basically in 2004 there was an outlook in nature, talking about liver cancer and basically 1 of the articles that was published there was the title to

try and try again, there's been many, many different studies and the first time, second time treatment, and they all turned out negative, they are all very good rational but the bottom line is that, you know none of the studies really could show benefit for patients.

so that is 1 of the reasons why, we believe that maybe alternative may be helpful and we think that immuno thr activities - -immunotherapy may be 1 way to go. i told you about the spontaneous immunity that's observed.

i don't want to say this is something very [indiscernible] but if you look at the number of populations, you look at the case at the disease with the most reports maybe just because there's a lot of asian repop ports and they may be 1 of reasonings but there is some

other reasons which are more most of the immune based approaches don't require a metabolism of the drug in the so can you actually use this approach independent of or also in patients with impaired liver function which is something very attractive and the other point

is, that this kind of treatment can potentially be combined with ablative therapies. so i thoughed you the pictures from the needle that the intervention radiologyst put into the tumor to destroy tumor tissue, i told you about the [indiscernible] where you ask me

about the radiology is actually gets into the tumor but there's a side effect and i will show you some of this, this is actually having some significant immunological effects because it causes too much cell death and because inflammation and potentially this, is what we are

trying to do is utilize this and use this approach to enhance immune responses. now immunotherapy is not new in the hcc, this is a summary that were clinical trials that were in 2006 wherever you can see an orange syringe on this picture, you can resent at least 1

clinical trial. the idea targeting the tumor cells which are on the lower end of this picture using anted bodies treatment using lymphkinase therapy bacterial cells dendritic cells,a i lot of different approaches, the bottom line unfort matily at this point

is that the studies were all negative. total of 1400 patients were treated without using cytokines and any kind of clinical responses. now 1 may say, okay, you chose the wrong disease, hcc is maybe not immunable to therapy.

well we found out early in 2004 that patients with hcc develop projection neurons or pions tanious antitumor immunity. so in this slide. what we show here is that in blood of patients with hcc, we can identify these t-cells that recognize tumor on the left side

and on the right side we find, weisk bakely look at antibody responses again against an antigen expressed in tumor in patients that are treated with either diagnosed immuno diagnose or treated with different ways of ablation. and these antibody responses

obviously date no question. the majority patients would not regret and die from the disease. why, why are these immune responses not strong enough. where 1 of the reasons is actually shown here, if we identify, if why look at the peripherals of hcc and compare

it to healthy controls. we identify the cell population which is shown here on the flow cytometry analysis which you can see dop there marked with the red square which is characterized by the cd3 and 4 positive htlr, now this cell population, you don't find if

you stained powerful blood transplantations that are healthy or a number of other controls as you can see here, the cell population is only increased in patients with hcc and you can find them both in the pishiveeral blood as well as in the tumor.

what do these cells do, they are suppressor cells. they can suppress an immune function and on this slide, i will show you briefly some data where we show that these cells if you take them in culture can suppress t-cell function in very simple coculture experiments and

they can also induce a different type of a suppressor cells, in this case, a fox p3 regulatory t-cells. the bottom line is these are cells we find which are image cells that are induced. now here can you see these are developed into the different

branches but in the presence of tumor and tumor derived factors such as gcsf, et cetera, they basically blot the maturation of these myeloid cells, the cells remain immature and then, we can further [indiscernible] i don't want to go into all these details but the bottom line is

these immature cells can be immunosuppression and these can effect the cd4 cells and the b cells and k-cells and et cetera and that is 1 of the reasons why actually, this is actually 1 of the ways the tumors have found to contact the immunity and that is 1 of the reasons why the

tumor specific immuno responses are not strong enough. now let me come a more clinical point or approach, i alluded to. so if we talk about imown o therapy and generate a t-cell that will recognize the tumor cell in this case in hcc, and you can see the t-cells in the

middle of this picture in blue, different ways of getting these cells and 1 way are [indiscernible] and i've shown you this work was done in the past and not very effective but now it's a lot of data indicating you can use ablative therapies so treatments that the

radiologyst do for these cells and combines this with other means such as check point inhibitors to amplify the t-cell function thereby priming immunity and [indiscernible] too much else. so we're conducting this in the clinical center and this is by

design which i'm showing you here we see patients with the immune check point inhibitor and ctla 4, and patients undergo tumor manipulation to vaccinate the patients and develop antitumor and use [indiscernible] you can see here, we treat patients that in

the majority of cases have [indiscernible], all standards of here and i will show you here now an example of 1 of the cases. can you see marked in red, the lesions that we follow in this patient is a 50 year-old male with hepatitis b in his liver

and you can see in markers with the redder o, the lesion which overtime got much smaller after 6 months, the patient developed a very mild coaliteis which is why we stopped the treatment but if we follow him over 14 months can you see the lesion reduced in time in individual cases

where the treatment may work. >> in theime own o therapy of the patients with the hbc 40, and you asked with the immune response [indiscernible]--with the patients or this kind of-- >> i will show you some of the data. >> okay.

>> i will show you second case and we get there will not be that many more slides, i will show you here, another case with why you can see reduction and pretty much in half and parallel the reduction of the alpha seat illegals protein if we look at the patient overtime, there's

more other papers responded but we find a response rate and here we look at lesions on the lesions which have not been touched by the virologist, and you can see that approximately 30% of the patients responded and showed that lasted at least 3 terms to 6 months.

here is a summary of the data again, obviously this is early but a response of the data of 29%. the treatment was pretty well tolerated especially if you target the therapy with the sorafenib, so we didn't find any adverse events related to virus

events, these are really autoimmune mediated effect, skin reactions and some patients developed thyroiditeis. we performed a [indiscernible] immune monitoring in the peripheral blood. huge markers we tested and i will show you very few slides

indicating that in the responders we see activation of t-cells that we can identify using different markers on cd8 cells, we can find, antigen specific t-cells on these patients and again why the number of antigen cells doesn't change the antigen specific

cells become more activated over time and then finally we also had some biopsies from these patients and here we can look at before and after and you can see that a number of cd3, cd8 positive t-cells infiltrated upon the tumor on treatment and did their job.

now finally in regard to the tumor they had regarding viral immunity. so what we did is we actually looked at the outcome of the primary hepatitis but these patients happen to have viral hepatitis and--that's why we can't determine anymore

hepatitis bdanda, but we can quantify this surface antigen and can you see it indicates hepatitis c indication and the idea that obviously you activate t-cells and the t-cells kill the infected cellings but this does not lead to any effects on the hepatocytes, side effects in

terms of liver failure or so. so let me just summarize this and come to the conclusions because i think we almost at the end. so what i have been able to show you that there is 2 more pacific t-cells that you need in the context of this disease.

you can activate them using choke point inhibitor, and the data indicating the ablative therapies can induce t-cell responses and i show you data that obviously this is not the end here because i kind of ignored the extrinsic factor. i've shown you data we have that

myeloid cells can suppress immune responses but the tumor may have to target them at 1 point and then finally i've shown you some data on the migration into the tumor and before i conclude, i need to show you the people who have done this work, so the clinical

trial is a collaboration with dr. duffy who is working with me and research nurses, fellows, et cetera collaboration with the center for radiology led by brad ward and the pathology office helped us with the analysis of the biopsies we had support from biostatistics.

and then there's research lab compartment [indiscernible] i hadn't shown you anything about our patient mouse studies we're doing but i showed you some of the correlative studies we have done where we study immune cells with patients with hcc. thank you.

>> yeah, thanks. so regarding immunotherapy, which revision criteria data did you use to treat the patients with [indiscernible] or ctl4. >> i would say the standard criteria we use for any other patients-- >> in terms of how many nodules,

and especially the liver function metastasis. >> so there's no limitationot nodules. but patients have liver function because i true i to explain to you that we cannot--we maybe said, we can't treat the underlying suroseis and it will

get better for the therapy in those patients. so our patients without cirrhosis. -- >> [indiscernible] even better. >> yeah, because usually you have [indiscernible] of hcc, with an underlying--

>> we have patients with-- >> i wondered how many patients the immunotherapy can be good for hcc? >> so let me ask a question, you're using alphabetta protein as a marker here. so i have an onk o beatle protein and so how good a marker

is that of hcc? in a patient who has existing liver disease: cirrhosis regeneration at all? >> okay, so, it's the best marker we have and we have certain limitations. you find an increase of asc in a regenerating liver.

so if you treat a patient o if you follow a patient with chronic hepatitis and you may see increasing numbers of hccover time if they regenerate through a certain time, through certain events if you have a patient with acute liver failure and they regenerate they will

get increased asc. so those are problems. obviously there's a gray zone if the value is higher than 400, then we call it a very high and significant [indiscernible] but the problem on the other side is that only 40-45% is hsc positive.

so there's a number of patients that never increase this level in the serum. >> so we find out that snorri was kind enough to send his power points which are all on the web site and they really are pretty self-explanatory for those who are interested in

looking at the specifics of some of the that can summarize they're really efforts to try and predict which are high susceptibility but survival patterns. they tend to be--point towards certain pathways and at the moment to identify and study

those pathways. so they're pathways that deal with cell replication, with apoptotic pathways and bioenergetics so it's a huge amount of data which are then analyzed and pointed in certain directions for further study and that's pretty much where this is

right now. , well we want to thank you very, very much for double duty. [ applause ]