Cancer Markers

so this is the last session. it started in 2004. so this is 2014. you can't hear me. i suggest, bob, you do something back there. at any rate, so we're glad that you're here and there are

roughly each time there are between 2 and 300 peoplewho are out there on the nih campus who are watching on their desk tops. so when you, and we welcome you, i'm sure the speakers do, to ask questions, either wait a minute until we get a microphone to you

or speak very loudly or maybe the speakers will repeat the question because i keep getting e-mails saying what were they answering. it's sort of hard if you know the answer but ou don't know the question. at any rate, so some of you have

not been here before but i just take a minute to point out what this structure is and i assume that everyone in the room knows that it's the most famousbridgein the world, right? that's the brooklyn bridge. why do we put that up there? well, for three reasons. one, because the picture was

taken by my grandfather. second, because it represents symbolically what we're trying to do, which is to bridge the major advances and problems for the basic biological mechanical mathematical science with major health problems. and that's been the topic of

every session that we've ever had. now this is 1883. those two gentlemen standing out there are undoubtedly surgeons. and what they are talking about is what are we going to do about cancer. because all we had was surgery

back in that time. and one of them's saying to the other, if we could only pick it up when it's early, we can surely cut it out. of course this is sheer speculation on my part, but from that point on, the concept arose meant that early diagnosis meant

better outcome. the only thing available in those early days was largely surgical. and then we come into the post genomic area with a whole paradigm shift. and it's a question of this premise that in early diagnosis,

and the question is what's an early diagnosis and what are you diagnosing. and that's where we are now. it's the area of search for risk factors, largely genomic, also environmental of course and also cancer markers. and the premise is like before

early detection will permit more effective treatment, drugs or surgery. in some cases, even as in the case of brca mutations led to prophylactic surgery before there's any tumors at all. this is an enormous spectrum that's changing since the end of

the 19th century. today's topic is really is, is this premise correct that was on the previous slide. the biology, the course of different cancers varies. what are the statistical chances of having a cancer given these different risk factors.

very importantly what are the markers mark, what do they have to do with the biology of the tumor. and of course can the action on the premise whether there's early diagnose sometimes can do more harm than good. that's really the subject of the

broad picture. and so we're going to begin with barnett kramer with prevention in the nci. we posted several of his most recent papers on the website. i encourage you to read them because as you'll see from his talk, they prompt a lot of

thinking that maybe you wouldn't normally think of if your life was directed to a very specific let's say reductionist research problem rather than more broadly clinical or even global kind of problems. so barry t in medicine at washington university at st.

louis. and has been ere a the nih in various capacities all related one way or another to this matter of cancer detection and cancer prevention. he's extremely well-known for the excellence of his writing he'll communicate to us today

and the provocative questions he raises. all right, bernie it's a pleasure to have you with us. [applause] >> thank you. thank you for those kind words. i think i'll start off with a story of the time i went to a

cocktail par and i knew no one except the hostess and so naturally when i walked if i gravitated toward the group that the hostess was speaking to. and got involved in the conversation. little by little people broke away until i was left speaking

with one woman and she said i have this joke, you see. it's so funny it will just kill you. it's about this doctor, you see. i said wait wait, i just want to avoid embarrassment. just so you know, i happen to be a physician.

and she said oh, now don't you worry, i'll speak very slowly. why would she say that? maybe because she knew about these concepts and how frequently physicians can be fooled by the highly counterintuitive nature of screening in particular.

and i'm going to cover some of the things that make this such a highly counterintuitive field to the point that many physicians will base their opinions about the screening and person experience can be misled by what their own two eyes are trying to tell them and their critical

experience. we're taught from day one in medical school that the wise physician learns from their own experience and that is certainly true but this is a case where even a wise physician can be misled by their own experience because even a harmful screening

test can appear highly effective to the physician and hence the controversy even amongst the health professions. a related quote in the field of cancer screening it's particularly important to be able to sort out what is known versus what makes sense.

a lot makes sense in the field of screening but some of that is wrong and we have to sort it out and that's where scientists come in. science as many of you know and i hope realize, is highly counterintuitive. if it weren't counterintuitive

we wouldn't need sciences. we could into -- intuit andsave a lot of time. this isn't the dawn of enthusiasm for medical scenting. the dawn of immediate skull screening probably goes back to a quarter century to around 1900.

there's a keynote speech from the president of the american medical association who talked screening for all sorts of things, including propensity for criminal behavior so that you could simply screen people for the potential of being criminals long before they ever

committed a crime or even thought about committing a crime. but the dawn of enthusiasm for screening in cancer date backs to this where dr. blood good from johns hopkins highly reputable -- that's the karchls -- cancer that's

practically eliminated -- immediately on the discovery of a fine body, of a fine growth in any part of the body. now, as you can probably see at least those close to the screen, this was reported in the "new york times." the newspaper of record.

then reputable and then reported in the summer of 1924. and so now well over three quarters of a century have gone by, we can look back and see how close to the mark dr. bloodgood was and he was basing this statement on his own experience. and we know that cancer was and

is and for some time looks like it is likely to be one of the most scarce diseases that afflict us and the world and if not the most scarcest disease in the united states. how could his own experience have misled him so badley by the end of this.

i hope you understand what the study biases and observational biases were that led dr. bloodgood to incorrect conclusions. that was the most screening test you can think of, careful history, careful physical examination.

although not more than some of the highly recommended tests you'll see in the newspapers like total skin exam. we're still stuck with total skim exam which is nothing more than be aware of your body, look for growth and so forth and bring them to the attention of

the doctor. again, we are lead often in our means to the same conclusions right or wrong as dr. blood good and i'm going to show you why i was off the mark. we even boiled down screening into oversimplified messages, public health messages and it

doesn't get any simpler than this. there's a cancer awareness stamp you can pay money for and get additional stamp money and the message there is annual check ups and tests. there's nothing about research, it's just check and take simple

tests and that is probably oversimplified. each year "the washington post" runs this contest. what is the shortest verbiage in which the most inaccuracy has been packed in the past year in the newspaper. a couple years ago the one that

won was you've done a hell of a job but that has more words in it than this which can be equally misleading. this is total lack of nuance and that's the problem with the field of messaging or cancer screening to an extent medical screening.

this is the egregious one the american cancer society had out there also caught some heat and they took down the ad. but basically it says in essence if you haven't had a mammogram then there's something wrong up stairs and you need something more than your breasts examined.

i think we've learned that things are a lot more complicated than that and we shouldn't overemphasize the benefits without talking about some of the down sides in the nuance of cancer screening and how to refine it by the end i'm going to talk about research

direction. the goal is not to do away with as a matter of fact we're not going to do away with it even if we wanted to there's so much enthusiasm for screening but we have to maximize any benefits that have to exist if they exist.

we have to find out if they exist and minimize the harm because the harm's always as i will show you. this is an element of fear m ongering. this is young germs and pre teens -- girls and preteens worrying about thyroid cancer as

if that's a bigger concern than doing homework what i'm going to do for the weekend. this is truly oversym played because the harms of screening all young teenagers for cancers probably outweigh the ben fist given the rarity of these diseases but there's the

messaging out there boiling down. the rest of the talk i want to go through the public health aspects because cancer screening, although it is performed in the clinical situation, often one-on-one of professional it's really a

public health intervention was the audience isn't single patient, the target audience is the entire public usually of healthy people. leon -- who is a famous epidemiologist from hopkins again chaired the panel here in a conference in 1997 on

mammography in young women, women ages 40-49. and the end of three days, actually months and months of sorting through the systematic evidence reviews and then listening to speakers give their different points of view and updated evidence, the panel

decided that it could not make an across the board recommendation in favor of mammography for all women in their 40's. rather it was a personal decision. they ought to know of the potential benefits.

they ought to know about the harms of routine screening. and then the visions of health professionals have not impose their own opinion on patients. they should work through the pros and cons with them. but their conclusions met with a severe reaction.

you're probably aware that the congress convenes and had a 98-0 vote to overturn the conclusions of the panel. if they mis-- senator said they were going to hold up the budget discussions for the nih, for the entire nih until the national cancer institute considered and

presumably overturned the results of the conclusions of the panel. it's the first time i ever heard of a 98-0 vote on an issue that that is as complex. but there was severe reaction in the audience including violence, people pushing each other and

declarations that the panel was committed hundreds of thousands of women to death with their he wondered why so much violence why so much resistance. and he came to the conclusion, which he conceptualized on this slide that people were operating on three different levels in the

audience before his eyes. the first level was, were answering the question what would you do for yourself or recommend to loved ones. you don't need hard and fast evidence, you're judging based on your own personal convictions or fears, whether your father

died of prostate cancer and your most fearful prostate cancer or whether your father died of heart failure and spent a year or two confined to bed and unable to even breathe easily or might have died of a stroke and hadn't been able to feed himself.

or to speak or to walk. and so you have personal experience that guides what you most want to avoid. the advantage is whatever your decision is, if it happens to incur net harm, it influences very few people. level two is what a health

professional is dealing with one-on-one and that is what will i recommend to my patient or client. here hopefully you're dealing with a physician who is at least has some familiarity with the evidence but we all have to admit that as physicians, we

look to personal experience as dr. bloodgood and sometimes personal experience can be very misleading. but at least it only affects scores of people, hundreds of people over any different physicians careers. but then level three, you're

dealing with what you recommend to the entire nation and sometimes to the entire world. here you're dealing with recommendations to hundreds of thousands, many hundreds of thousands, sometimes many millions of people, and here the stakes are very high as we'll

get into as we talk about some of the national experiments that have been undertaken in the area of cancer screening. here if you make the wrong recommendation you incur lots of fun and this is why the level of evidence you hope to be the very strongest and this is why panels

such as the institute of medicine strongly recommend that there be a systematic evidence review with a formal analytic frame work rather than simply depend on experts or specialists who deal only with the numerator not the denominator. this is a public health

intervention and it disease with the denominator. sometimes we say medicine to the extent that it is a science is a science of the numerator whereas public health is a science of and sometimes it's a great divide between people who devote themselves to the numerator and

devote themselves to the denominator. as a matter of fact there's a great divide between advocacy groups that are disease specific. they're in the numerator. times they realize they have popped out of the denominator

and are the numerator and they have a different perspective over what recommendations should be given to the denominator based on their own personal general advocacy groups like the women's health organization are you have to weigh a lot of the pros and cons because it is a

bit like the lottery. there are very few winners in the larry. -- lottery. that's a loser and as a matter of fact in the lottery mathematicians tell us the way the lottery exists is there are more costs than benefits.

that's why they run the lottery because they know they'll pay out less than they get in terms of the cost. in terms of cancer screening it's not $15 or $10 here. when i talk about costs i want you to think of human costs. major surgery, exposure to

human, proven human carcinogens. that's what's used to prove cancer, human carcinogens so they're down size. the costs there in this lottery are a little higher in space. so, i'll just go through the core issues in screening and prevention.

and that is, it's difficult to make healthy people better off than they already are. most healthy people don't need an intervention. and yet it turns out that it's not hard at all to make healthy people worse off than they already are because they are

never destined to pop into the numerator but they are exposed to the same costs. in the denominator you've made them worse off. there are a variety of ways you can -- therefore benefits are important ones putting large numbers of those people in

harm's way and those are the target population for screening. not the people who ultimately are going to have the disease. so for that reason, there are formal analytic frame works i alluded to and this is one i used by the u.s. preventive test which is sometimes called the

test in the agency for healthcare research and quality. so these analytic frame works are designed to make sure that we avoid our own -- and mental short cuts. the hallmark of any subspecialty is of course its language. they develop their own code

language but also the mental short cuts that they are trained to take. and this is true. surgeons have their own mental short cuts and radiation therapies on the short cuts. and so do physicians and medical oncologists.

the shortcut is probably not the right shortcut but the short cut is that a surgeon will tend to think that cancer is always localized and then very very slowly. whereas a medical oncologist probably also incorrectly always pins the thing that cancer is a

systemic disease, period. the trip is probably somewhere in between and that's why we combine our therapy. those are short cuts that each subspecialist takes as they move through their day. they are helpful because you got to go to sleep at night.

and you can't obsess over every decision but sometimes they can be harmful and this is one area where they can. the left side of the slide is the healthy population and on the right side is where the goal is. that is improving actual health

outcomes. health outcomes are not stage of disease, they are not tumor shrinkage, they're not ability to do surgery on more people. they are actually how the patient feels or functions. dead or alive, quality of life and of course that they suffer

from cancer or not. and the most direct and efficient way to learn where the screening tests were to achieve those goals is the direct test of popular slide. and the most efficient way is a randomized control trial. short of that there are too many

confounding factors that distinguish people who get scrarynd from those who don't get screened or tumors that are screened compared to symptomatic tumors. and sometimes it is the fastest way of getting it and if you don't do a randomized trial or

warn for screening test, sometimes you can wind up behind the eight ball because people make up their minds by the time the screening test is launched. all the intermediate end points are intermediate outcomes because they are intermediate, not the ultimate goal.

and then the testing and subsequent treatment and adverse outcomes and we can't lose we can't afford everything. the healthcare dollar is to our disappoint elastic. we can diminish the health of the population if we take resources from things that work

very well and divert them to thing that work very little or even not at all and worst of all they actually have a net harm. and in some cases we are actually probably doing that in cancer screening and i will get into that. but at some point we have to

learn. now nations that have national healthcare systems know very well that the two questions doesn't work and should we do it are two separate questions. in the united states, we traditionally have had the luxury of assuming that those

two questions are one and the same. that if it works at all then of course we do it. but we're learning even that isn't going to hold up for very much longer. whole states are going bankrupt because of medical care costs.

what fooled dr. bloodgood. one of the important biases is selection bias and length bias sampling or shorthand and is length biased. so actually bias occurs because not everyone who could be screened is screened. and the ones who decide to be

screened tend to be fundamentally different. and healthier from the ones who aren't screened. people who come in for screening, number one, are generally wealth thursday and generally insured and so they have access off their system

that others may not. they are generally very health conscious and so they are searching the internet every 20 or 30 minutes to see if something else came up, popped up on the internet that can make them healthier should they be eating more olives this week,

drinking less coffee this week or whatever happens to be. and so these are people are going to be healthy irrespective of whether or not they actually get screened. these are people who drive volvos because they don't want to die in car crash.

and they're wealthy enough to afford volvos and they don't drive around in corvette stingrays and so forth. this is going to be a healthy population. they take multivitamins. they exercise. so whether or not they get

screened, they're going to have lower risks of a whole bunch of chronic diseases including we had the tent to include the selection biased as the screening solved the plco -- which was conducted through the national cancer institute at screens around the country,

155,000 people around the country half men half women screening for those diseases. we looked at people characteristics people who are health conscious enough to sign up for the trial the randomized trial to be screened or not be screened.

and so we compared it to the national health interview survey his which is the general population database. we found out that the people who signed up for the trial had a far lower prevalence of smoking. smoking was one of the biggest drivers of almost all the

chronic diseases out there. regular physical activity. they actually start a lot more. they were more educated than the general public. and they had less court morbidity than the general public. so you can't compare screening

in this population to not screening in the general public because there are too many powerful confounders that would make you think that screening works even if it doesn't. and an important fact standardized mortality ratio in the plco participant, and the

standard mortality ratio is nothing more than the ratio of the deaths observed from each of these causes to the death of the general population and you see highly specific significance. every cause of death was lower in the people who entered the trial.

even though we weren't, there was no intervention for any of those other diseases besides the tlcl cancers. the ones i find the most using is if you signed up for the plco you had a statistically significant 35% reduced risk of vying of injuries or poisoning

and we had no brochures how to avoid injuries or poisoning. this is just a group that was less subject to totally unrelated causes of death. in the meantime bias occurs because any screening test will advance the data of diagnosis. if it doesn't do that we don't

even call it a screening test. there's a guaranteed survival time built in for screen detected cancer. and you cannot compare the survival. this is what probably fooled dr. bloodgood the most because he was used to his patients

dying very quickly after diagnosis of cancer. now after physical examination survival time after diagnosis was much much longer even if they happened to die on this slide on the same day of the same cause. he wasn't able to notice that

because he wasn't looking at the data from his experience with when that numerator was going to be misleading. length by sampling also fooled dr. blood good. it turns out that screening tests are far better at picking up the slowest colon connors

than picking up the slides. this is almost a geometric certainly. i had depicted a population very fast growing cancers, very short arrows at the top half of the slide and the other half of the population very slow growing cancers -- and you can see that

a screening test enriches the population of diagnosed patients who are the long arrows. why? because they are more long arrows are out there for a longer period of time. the patient is very asymptomatic so you pick up the slowest

which converted a healthy person from healthy to a patient and subjected them to many therapies disease reservoir. the more we learn about the biology of cancer, the more we know there is a reservoir of things that a pathologist willing to call cancer but don't

act like we generally think about cancer. and then activities leading to a detection particularly screening but it doesn't have to be concerted screening, doesn't have to be intentional it could be the ct scan of somebody that complains of some

abdominal pain or discomfort. and the ct scan can pick up all sorts of incidental findings that sometimes go by the name of incidentalomas and a lot are not maglinant but looks like cancers. it's a heterogeneity of cancer this is oversimplifying cancer

but we sometimes say there's some justify koition but this is definitely over simplification. cancer starts with one errant cell. your cells are constantly diverging and accumulating mutations and then suddenly one cell goes bad.

that's the cancer. it has a more constant bubbling time. it doesn't, the cells don't die, don't go through apoptosis as frequently. so the cancer grows and grows until ultimately it's large enough to cause symptoms, and

then often at least large enough to create total body burden that is lethal. but in the meantime along the axis of time, cancer is a disease of aging, and so as you age, even if you have a cancer in you, you are prone do dieof9#ã± other causes.

as my father used to emphasize to me you're never going to get out of this world alive. so something's going to get you. and so you have to keep in mind what it is that's most likely to get you. and so a fast growing cancer natural cancer is likely to

cause your death than other causes. slow growing cancer can still you would like to intervene if you can to the extent you can and avert a death from cancer and have the patient to go on and die of other causes. but we're learning that they're

very slow growing cancers. so slow they wouldn't cause -- there are cancers that spontaneous regress. even teurnlings like neuroblastoma can do it and lymphomas can do it and spontaneous regression. we have to keep in find cancers

don't always grow competely in one direction with one disease. that's over diagnosis. from what i've already said, cancer screening test by and large are far better at picking up these than they are picking up these. but worse picking up these.

those are ones that we would really like to have a cancer screening test pick up fast enough to intervene. but unfortunately we're stuck with most of the screening tests in missing those. what is the evidence of the population level.

what is over diagnosis. okay. look at the population level. well it's a rapidly increasing incidence of tumor. more and more diagnosis. but no differences in chance of dying of that disease. here's a classic melanoma.

and that is it's one of the fastest rising cancers in terms of incidence in the united states and that by the way tracks the number of skins latches. you can produce kind biopsis in the united states and it is going up very rapidly, almost

all of the increase has been early stage disease as you can see in the bluish. but in terms of late stage incidence, the real killers there's been very very little change. in terms of mortality, also very very little change.

now a perfect screening test will pull late stage cancers out of the future into the present, right? and so after enough times gone by, you should see rapid increase in incidence, this cancers not just decreases a little bit but go away with this

much increase incidence, and so whenever you see that it doesn't, you have to start thinking about overdiagnosis at the population level. this is the largest human experiment i think that we've ever done with the possible exception of giving all post

menopausal women in the united states hormonal therapy and we got burned badley that way. but this is the experiment we did on men instead of women so we're an equal opportunity society and here without knowledge in hand, that there was a net benefit to psa

screening, you can see what happens even with a simple screening test that isn't all that. we know it's not that very and we dipped into a huge reservoir of silent tumors that looked like prostate cancer and you can see what has happened.

over that era, it's estimated that about 1.3 million men who have never been diagnosed with prostate cancer have been diagnosed as a result of screening efforts and early detection tolls that are only we have to say are pretty crude. what's happened to mortality.

the risk of dying went up, it went down. it's now down to a little bit lower than it was in 1973 but it's not far below what it was in 1973. usually when you hear that screening has gone way down it usually measures obviously

measured from that lower baseline. but what has happened over the last century or quarter century as a result of that? well as i already told you survival has gone up dramatically with prostate cancer because people have

disease and cure rate has gone up dramatically because again we're throwing people in to be cured. so the trick is and peter will develop his whole talk to this. how do you distinguish the ones that really needed treatment. now some people look at that and

say this is evidence that is not how screening works. as a matter of fact i've seen a paper that reported regression diagram plotted the density of urologists per hundred thousand people in populations and shows that mortality rates for prostate cancer went down.

the population of neurologists and that was used as evidence that screening works because they said that's the thing that is neurologists like to participate in is screening so they like to -- but there's another paper out there in the literature which is a classic,

they did the same thing for pairing storks in the greater berlin metropolitan area. and it shows that fertility rates dropped as the number of pairing storks were dropped as well. and in yes they reported]$ and shows that the stork theory

rather than sexual production should be the dominant theory that is taught in public schools. this is mammography. this is what mammography has done in the upper part of thegraph you see the increased rate of koreaning with mammography.

so it maxed out in the 80% range. and in the lower portion of that graph you see early stage disease and late stage disease for breast cancer. you can see that the trends have been dominated by early stage disease, ie screen detected

disease. and very little decrease in late stage disease, about an 8% decrease in late stage disease. and this is only when early stage disease was all invasive but for carcinoma insitu would make that worse where screening is greater in picking up and --

whose natural history we don't need to really know accounts for that 25% of mammographically so called breast cancers. it turns out by the way all the increase in breast cancer is all of the decrease in late stage breast cancer is restricted to regional breast cancer stages

three. no deposit for the most part. no decrease whatsoever, none in metastatic disease which is little bit disappointing because enough years should have gone by that if you were pulling metastatic disease out of the future, they should have noticed

in the trends of metastatic and -- therapy is chlt notgoodoc)ij for metastatic disease. it's quite good for the intermediate zone of breast cancer as has been shown in multiple randomized trials to decrease the risk of dying of breast cancer.

and so even what we think is the magnitude of benefit of mammography may not be quite what it was years ago because all those trials were randomized trials were done before -- therapy was being used routinely. now we know and it turns out

this is the irony the more effective your therapy is for a little bit later stage the less you have to depend on screening to achieve the exam result. i shown you traws pate and breast cancer and melanoma. the same is true for kidney we don't screen for them but

there's a lot of ct scans and they pick up small tumors that pathologists are willing to call no substance of change in the risk of dike and the same thing is true for thyroid cancer. this was being teenagers as being encouraged to worry about thyroid cancer.

we're challenged with cancer screening is predicting which of those lesions that are detected by the screening tests focuses on screening tests. everything seems to be on the most sensitive screening tests and picking up the most you possibly can.

peer is devoting his career to that and devote his entire talk, so i'm not going to get into the details therefore but we need to distinguish those tumors that are screen detected that need treatment and even better that not only need treatment but benefit from treatment from

those that don't need treatment in the first place. how do we do that? this is where the scientific community comes in. we need to distinguish screen detected cancers from clinical cases. too frequently physicians don't

even correct that information. we collect no information prospectively from how humors are diagnosed. the oncologists don't even care. they care about stage one versus stage two versus stage three versus stage four because that's how they guide their therapy.

but a screen detected stage two may have a far different biology from a clinically detected stage two and so forth. and as a matter of fact, that's true. we've learned that from molecular fingerprinting and natural history when we have the

opportunity. so we have to determine the molecular patterns of the two classes of tumor to try to distinguish them. we have to look at targets for primary prevention because primary, if you're developing prime prevention you want to

attack the real killer chances. that is you gain less from a preventive intervention that only decreations the incidence of non-life threatening. you gain more when you have an intervention that goes after the symptomatic cancers or the life threatening.

and we also have to correct normal organ around the tumors. cancer is not just a cellular disease, it is a tissue-based as a matter of fact many would say it's a host based disease and a population-based social disease as well. at many levels.

we have to understand what drives tumors. but at the molecular biological level you have to understand not just the self what's going on and around. so i have taken you across the entire analytic framework from left to right and showed you

where dr. blood good was misled and why we use this analytic framework to avoid this problem but i haven't covered the adverse effects. so i'm going to go down very quickly the consequence of we all know this. i would have to emphasize this

to you. the good screening is reduced risk of death from targeted cancer for screening and the most sufficient way to get at that with confidence is a controlled trial. not observational studies, not personal observation that is

subject to compounding. the other is reassurance. some healthy people feel they need to be reassured they are healthy. they worry well. but it turns out that most screening tests are, don't offer any real useful information when

you look at it mathematically to somebody who feels healthy because the negative predictive value is very very very low. that is if you have a 99% chance of not having cancers, getting a screening test will increase that chance but somewhere between 99 to 100% maybe as high

as 99.2% or something like that. 99.5%. but that's not a whole lot of information for particularly healthy person. now, there are vague consequences, false reassurance when you have cancers, ignore symptoms.

false alarm. lots of false positive tests and harms of the unnecessary work up. the test itself -- perforation, infection. detection and there's a lot of sepsis but it's apparently coming out more and more with

pipe sees for prostate cancer. the touching of a lethal cancer without changing the outcome unfortunately that's the case for most lethal cancers because we don't take the mortality rate of lethal cancers down to zero. and the lung cancer screening trial the reduction on cancer

mortality rate was somewhere between 16 and 20% on a relative 1k5eu8 leaving all the other connors that were unfortunately skill just a lethal and screening didn't do anything. detection of non-lethal cancers in diagnosis resulting overtreatment.

so another thing we have to learn is how best to communicate. posters in airports are not the way to do it. sound bytes on television is not the way to do it. it's more complicated than that. this is the way we tried with

the screening trial. we added up the benefits and harms. the benefits are about a positivejw;< trial. and it's actually three in a thousand. for every one thousand people that are screened over seven

years, we estimate our best estimate that's our three fewer best for lung cancer. and actually five in a thousand died, fewer from all causes. but in exchange for that, these are the numbers of false positive, 223 out of that thousand these are the numbers

of false positives that lead to invasive procedure and two is the number of a thousand and a main complication from that cascade. for mammography for women age 50 and above the benefit is somewhere between .3 and three women will avoid dying from

breast cancer if they start screening in their 50's over the next decade. the harms are that more than half of them are going to have at least one false alarm. seven to 100 will undergo a biopsy and between 3 and 14 are not able to diagnose.

tt means their tumor never would have come to medical attention and hear going to get the same full court press therapy anti-cancer therapy as well which often involves lumpectomy, sometimes massectomy, involves radiation and chemotherapy and hormone

therapy. by the way for the research community and health professional community, i'm going to leave you with this one last slide. the research community and health professional community has to learn this lessen.

you cannot shoot first and then start asking questions. unfortunately that is what happened to us with prostate the world's largest experiment or the largest experiment in our own country was launching this passe screening messages, campaigns and on and on and on.

all societies built their messages on one thing. you saw the trends that resulted from that. we are still struggling to figure out the benefits to two trials have come to divergent opinions. ones done in the united states

in a principally screened population show no benefit, all harmed. the ones -- showed benefit also a lot of harm. we're still struggling but the problems with the trials in the united states was we had already made up our minds.

we shot first and there was a high contamination rate. people who are randomized not to be screened felt they were randomized for the wrong arm and so that probably wanted the statistical power to see if there had been a difference although we saw no hint of a

difference. so that's the lesson to the health professions and that i think is the segue to peter's talk about how is the research community going to get us out of this bag that we have put ourselves in. in prostate cancer.

[applause] we'll take a few minutes for questions. >> [indiscernible] of the new york files times a few days go- biased medicine by reimbursement rates to more screening and less therapy is still a consequence of the love affair with

screening that is continuing to affect medicalractice. >> yes. and he writesik3n+q that. as i said the intuition is so strong and the emphasis. as a matter of fact herere quality indicators, not whether by which a physician is judged

sometimes. not whether they had a full informed discussion with the patient and allow them to make the choice but whether or not the patient got sent for the screening test or whether or not where they gave the patient prescription or screening test.

in some ways i think that has perverted the incentives in the health professional community. especially, and i'm, i want to say i'm a strong pro proproponent of the healthcare act -- it just has an accelerator and that is get more people that were not able to get care into a

healthcare system. but there still needs to be a way to get wiser about therapy. that's not ratiing -- well we already rationom care. we do it basically -- but it's not really rationing, it is determining benefits and harms and deciding that we are going

to make sure that every person or more people get the things that are proven, have a lot of benefit and not to disincent physicians to do the simplest of wrong things. the point he makes and you are obviously making as ll s a crucial one as we face the new

healthcare, i hope healthcare system. now we haven't had national health system, we've had a national health situation that we're living with but i hope your implications are on target. >> other questions? this is kind of discussion

question. do you think it would be good to introduce new professions like [indiscernible] i'm just trying to invent it so the person who could haveet a better informed kind of helping patient with some decision regarding whether to do the screening or not.

because having a lot of deaths kind of marker that currently exist physicians probably will not be in a good position. >> y. so you're referring to a phenomenon known as the crowding out. if you rely on your primary

physician -- if they spend their time going through all of this complexity even for one decision they used up all the time that matters to the patient. that is why you decide to come here today is there something really bothering you and can i intervene.

that's called the crowding out phenomenon. it's easier for a physician to check check check check. my internist does it all the time and i've had arguments with physicians or discussions with physicians where i say don't order that test.

and i know he's gone rounds with the local hospital recently and he's learned everybody gets vitamin d level or msa or part of his routine screening test. and i say i don't want it. i think that the benefits may not be -- but you can't depend on private physicians.

and welsh is a screenologist but there has to be a better w. to reach informed decision-making. it can't be do whatever you want. it can't be i will get screen if i were you. it can't be a patient with late

stage pancreatic disease and therefore i screen all my patients. there have to be> there might be might be group lectures or pamphlets more nuanced or encouraging nca-related fact sheets. i chaired the nci board of pdq.

we don't say get a test we don't say don't get a test. we never say that. we say these are what we know of the benefits and magnitude of the benefits these are what we know about the harms and the magnitude of the harm. this is what we know about the

generalizability that is just because it works in an academic center does it work out there in the general public. and we have to do it straight through in one direction you're absolutely right. >> some of those people),: in the pro screening camp tend

to say it's not the screening that's the problem, it's that next decision. if you come up with a positive, that's where we should have the education. and not as to whether we screen them. >> we have to attack them that

way but i think they're incorrect because that's not what we do. the evidence is ony side and that is giving information. by the way not all information is good. that's an argument that information can't be bad.

not all information is good. especially if it's misleading. we have gone to war because of information. that we thought wash< reliable. and you know, thousands if not hundreds of thousands of people were killed because there were some misinformion tre.

so we always have overconfidence in the information and think we can think our way through it if we're only given information. but we're headed into this even worse. whole genome wide screening is going to give us data. and so there's data or

there's knowledge is the next step which doesn't always breed knowledge and information and naj doesn't always breed wisdom. so i don't think we can assume that it's okay. there's no harm in getting the aside from the fact that sometime getting the information

itself is harmful. by the way labeling is harmful. you convert somebody from healthy to a patient that has implications or their employment. employment rates go down by the way in cancer patients. almost across the board.

under employment and unemployment and currently we get most of our health understand at access healthcare if you're employed or unemployed we may have access to healthcare or go into a different healthcare system we don't want to be in.

that's one thing. labeling also is an accumulation of data just the diagnosis itself information you have it and you dot need to be treated. suicide rates spike and so employment drops, suicide rates go up including proste cancer

by the way lasting for six months to a year. labeling itself can be harmful. and the other thing is the test itself can be harmful, radiation accumulator over the years has a harm and also as i mentioned some of the tests are associated with perforation.

some of tests lead to the biopsy of the prostate glad, you go through an era for people for reasons we don't know for sure maybe it's a lot of antibiotic exposure have super bugs and within 30 days of admission into emergency care units with bacteria.

we're at an arm's race of microbe -- but we're not as good as it as they are. they can do it in hours. it takes us often years or even a decade. even the information itself carries with it some harm in it and i never like to forget hat

labeling itself hurts as well. >>7=s it would seem intuitive to use your word that countries with a national health insurance can cross the bridge easier between having made a diagnosis for ichthere is effective but the cost for therapy is totally out of the reach of the

vast majority of people. in my field if you vaccinated everybody with hepatitis b vaccine, if you gave all the hep c patients the new protease inhibitors, you probably eliminate a huge proportion of primary cancer of the liver which is a killer disease.4!3

but that's not going to happen because the costs of both, particularly the latter are through the roof. so in your thinking, and these various panels and discussions, to what extent do you go into the issue of the costs that are involved when you make a

diagnosis. >> so of course you know that there are rules in place where the u.s. federal government doesn't, is not able to make some of those decisions. as a matter of fact some regulations specifically prohibit agencies or departments

from making physicians based on costs. and so we're eliminating, we're sometimes limited in decisions we can make in that respect. we're going to, i don't know if we'll ever get there but now for hepatitis c virus that just came out which apparently cures the

hepatitis c. i mean that's a break through. a thousand dolls every time you swallow a pill. there are countries that are saying a thousand dollars every pill and you got to take it for how long? well two months.

oh well who isgoing to pay for well we'll pay 80 percent and you pay 20% and that's a problem even in our own society where people can't afford it. some societies know,ã­ know, pap smears were a major break through life saving

screening test. you're looking right at the organ that gets the cancer. it's that big. you focus all your energy on you scrape the cancer right off of it if that's where the cancer you look at it right under a microscope so everything is

working in your vor. we still have a lot of overdiagnose but that was a true lifesaver for one of the common killers of all women in the world. why don't countries do that? are they stupid. well there are many countries

that look at the cascaded of the events to the pathologist that's skilled off to the gynecologist who can do the surgery and the equipment is easy to do it and the follow up and so forth and say there is no way in the world we could possibly do that. their hope is either visual

exination wher you take a layperson who is trained to look at the cervix and stain it with acetic acid and there's the vaccine and that's why the vaccines will hopefully be a game changer. that's why they pay us feds big bucks and that is to think of

all the possible strategies and figure out which ones are going to achieve the ends that you want that you want in the most efficient way. and another game changer we give free vaccines to young girl in the united states and boys in but that costs a lot, costs a

lot of money and a lot of countries can't possibly afford it. it's a realeã¡ game changer when we're talking about and being involved in and that is less than three doses. if you could get, if you could prove one dose was as effective

as three or as two, that would be an amazing break through. think of the -- we have to think -- hpd screening may gee a stop gap measure but in the distant future maybe we'll have multivarnt vaccines, one dose and you're done. that would, yes, sir.

>> you don't make much money making the vaccine. thank you very very much. i think we should move along. our next speaker is peter pinto. who is a physician and he's trained in urology, urological surgery and he's a fellow who got his training at johns

hopkins and i heard just before this that he came to the n to do research and do clinical work with prostate cancer so as to eliminate the psa. well we're going to hear more about this so peter thank you very much. and we're also grateful if you

want to introduce your patient. so first of all i want to say thank you for this opportunity. we need three hours for this on multiple days. >> like the story how long can i talk. you can talk for 40 minutes and then we go home.

>> it is just amazing because this is hard hard work. it plays with emotions. as scientists, we're designed to look at the cellular level what is happening. or we lose the forest. or we forget how important it is that what we're trying to do

with best intentions can also cause harm. so i give barry a -- bernie a lot of credit. sometimes they're looking at opportunities for a young clinician physicianbh scientists where you have mentors and people around you.

there are questions that formalize that i don't give up on screening. i think we going to screen but we need better tools and better devices and better opportunities to screen more effectively. and so you can take away from the past hour this well why did

i have this done. may patient came to me who is going to speak shortly. i always wonder why did i have this so dr. pinto 25eubgz care of me and let others go with observations. i may gave you the harms of treatment and gain the benefit.

we never know today. in my how was we deal with the patient the best we unless the emotional factor that's hard to deal with. separate that out. my lecture today will focus on what we're doing here in the community to try in some small

way affect a more efficient screening method. when win gave me this opportunity to lecture i wanted to make sure we still had these numbers. you can see here on the slide yes truly overdiagnosed. and not to repeat ourselves from

the previous lecture yet we don't improve a lot in the way;e of mortality including mortality. i'm a urologic surgeon. i had engaged in research years before this to try to show that there's better opportunities besides psa.

this is what we are told, that is the screening is bad but the use of psa. now, after that came in particle, a publication that said well if you were to randomize patients to operate but do nothing, and followed them in this case for 12

years -- there would be a paper trail. this came soon after that. at least in particular for what we call the overdiagnosed low grade tumors that we found as we really had not improved any. you can argue and we'll definitely postpone that.

you can give us a [indiscernible]. close. on the edge. so what of the patients 5,000 were eligible. all of them declined to be randomized to surgery but there

were 700 engaged in this va and over a 20 year period -- we really didn't see an improvement in death from this cancer. but what we did see, we did see a clear evidence of harm in most patients, in particular in erectile disfunction. both patients got the harm up

front and the benefits were unclear. they argued under powered only 12 years with a slow growing disease, this happens in 20 years and this occurs over and again. on the heals -- not using psa but surgery, i decided to cut my

talk short and summarize that we don't need the screen for prostate cancer. we don't need to even discovered it, treating it. this could be the death of an entire medical profession. so with that, my father gave me a call and said jokefully and my

wife, it was on a voice mail and she recorded it on a device. it says peter the room in your house is still available to you, you can come home whenever you want, we heard about pda screening and it's not being helpful. you can come back and work with

us. i said we're ahead of this. i knew this was going to happen and actually i'm doing well at the nih. i'm going to stay on and won't come home at yet. the reason why -- those in the audience psa, it's a blood test

that can suggest that there's cancers in that patient which leads to a blind random biopsy.0+"t)uã¡u just take the organ inthis case prostate and you just hit it a couple times in this case 12 times and you often miss tumors and detect cancers. in essence i think the solid tumor that i know of that is

routinely diagnosed with that imaging for the hope of hitting the humor. you want to do this with colon cancer and other tumors. we just heard about pap smears and the visualization of the surface. so these biopsy rates fall

short. if you did it 12 times or a hundred times you still won't find all the cancers. you're never sure when you tell a patient did the cancer or did you truly not have kamples. this is going beyond the once we have screened, what are

we doing. one of these folks is the well do i give the reassurance to my patient if he is in craning currently to forego future biopsies, should we then not even screen or if we do, perhaps they will fail my patients. so that's why the collaboration

here with many institutions, including peter -- and the imaging programs and colleagues in radiology and myself and my colleagues in medical oncology have come together and said shall we bring some devices on this catch puss make some devices of image tumors within

those in the group have dub this before. there is imaging. he'll told by my neurologist he needs ultrasound to see the that's not the case. more than half the time the tumors that are believed to be cancers are not cancerous.

this really is a gray scale ultrasound scale. urologist physician. we disguise the needles and make sure we're not hitting the prostate. i was told these are the images of mre. this is what we see.

we kicked anything. if you look at this, it's too bright in the foreground, dark in the background. it's not this is all technology but when we see now today is more in detailed visualization of the anatomical of the prostate.

we have in our pocket our cell phones have enough contributing power i would take my first desktop. we can advance with maybe opportunities here to improve how to detect these tumors. and the anatomy there has details that are currently not

cancer specific but just anatomically specific. but we hope to glean from these images tumors. so what we have is not just a single mri that you can get. in the discussion prior to this meeting we were discussing about academic of excellence across

this country. this technique is hard to replicate. it performs well here because the tumors has been developing this and improving on this for decades. but all other imaging tests, it will improve and go on into the

community,, it just takes time. it's not just one sequence. it's not just a t2 phase. it's actually a functional imaging parameters in mri. we call that multiparametric mri. that's a simple test not a mammography.

this is a somewhat expensive 40 minute examination of the process. working with the details because time didn't permit this. i'll hop on sort of a few of these functions. imaging, it actually looks at the ability for cells to crowd

and effect the motion of water. what you can see here is in this case a large sumer. you can see it now in the t2 phase and weighted phase is the -- phase on mri. the sequence of this could be a typical contrast enhancement where while [indiscernible]

bring blood supply in quickly and those are areas of hyper intensity. and then actually a true functional image is -- where you could and actually different levels of colon citrate to see if there's tissue that's cancerous or benign.

again folks of this lecture today but when you take all this parameters together actually performs very well. we can then and through the prostate and pick out those areas of tumors and pick out the aggressiveness and i'll get7 that in a to you moments.

this is ground breaking technology but my mentors were direct, they value this by 10, 20 years ago at this specific level. so we can actually then score and our radiology colleagues have a level of suspicion. this is not an automated system.

this isn't an ekg machine. you get the machine and gives you a reading. it requires a physician to interpret that. we're working on technology here to semi automate these. and the particular person at the nci that mentioned additional

imaging tools in this case it's actually a polarizer for -- to look at the metabolic cancer and that can be viewed in the patient in conjunction with mri for anatomical detail and give us what we believe might be the opportunity to see the biological aggressiveness of

and this is exciting work for which we're going to link to actually the profiling with a colleague of our hours in michigan working together on this in this aspect to see if we can look beyond imaging but the biology of the disease. so when people hear that

minuting for prostate cancer it may change how we maybe screen it, you have to actually show that it works. so protocols here on this campus where patients who had diagnosis of cancer who then came to me for surgery but first were imaged with our mri technique

are able to then go ahead and analyze slice by slice the prostate mri and the surgical specimen. the specimen pathology being the gold standard. we look at the past literature previously didn't have a nice qualitative connection so they

couldn't determine if they were in the same slice imaging and pathology. as a result, you were unclear as to how well mri performed. to solve that, and this is just an examplehi of going fromimaging here to the specimen. but it's to make sure that we're

in the exact same orientation of mri pathology for each individual we created often the mr software a customized mold or a models of this prostate. it actually got so good that we couldn't go into it, the suspected tumor location based on mri, and then pathologist to

actually whole mount slice the prostate at the point where the mri of the organ. so we forced pathology to actually cut it to believe tumors work and we forced pathologists to -- and this really stringent criteria for kind of correlating allows us to

do two things. allows us to=k at a high levelof competence procure fresh tissue for profiling like weather doing now. so our colleagues now are scientists and ph.d. colleagues have now really rapid rna detected quickly so we could

procure in a confident manner. and then as i mentioned before sequence these tumors going forward and see if we can see some biological activity among imaging. this whole process then came together over hundreds of patients to say well, can we

then have confidence. is there a positive value? tumor detection throughout the whole mri. this came out a few years ago. and the t2 alone performs well but not great and we listed tumors but we add sequences, we have sequences we have a.

consequence [indiscernible] i want to be able for a program like yours who have a suspicion of cancer i want to rule out again it performs overall the performance very well. and this basis started our flaws fee of well if mri can see tumors how

this was through a crater that -- and this is really like i said before it could not have been done anywhere else. we shared patients. we are not held to reimbursement issues. we weren't tied to seeing a patient -- went ahead to have

the same patient we shared them and we created with our engineering colleagues pathology included a device that can go ahead and sample what the mr believed was a tumor. this was the early days in 07. and again at this point, we couldn't see any of the

treaties. we were just focused on this one device. was many sure if it helped or hurt but we just wanted to sample those tumors specifically in the mr areas of hot spots. machinery not community based or office base and definitely not

physician friendly. we have engineers sitting behind you real time patients on this table. the platform today almost seven years later is a more slipped down version that may have portability to the community. we hope very soon.ã‘j

we use a tracking system to actually guide needles into what the mr -- mri is the magnet. anything ferrous is not -- if there are non-ferrous biopsy technique not incorporated inside the mr. it's a closed system. we felt if the mri sees a tumor

well then the technique is comfortable in the office setting on a typical machine fused images together, bring mri out of the gantry put it on the machine in an office setting made it possible. of course we did preclinical work and we have credit on

the -- at this time many of these teunlts have gone through their own program. in doing so what you see now is actually a real time ultrasound image of a prostate used for blind biopsies. where the mri is being ghosted on to it.

the current choice of it being aligned. this is the software created by our engineers and the clinical team helped refine the use of this to allow us to go to create the mri interest, the tumor interest spots on ultrasound. by doing so they actually

move -- this is the latest version. this mri is a static image acquired possibly weeks or months ago. this ultrasound minute real time with the probe and the patient and the mri is moving with ultrasound.

the area of suspicion is identified in this case called the target in one spot we can go ahead and localize it and pass a needle into the area. that spot is right there. of the horrors you hear because we perform many by as. if you don't know where the

tumor is you have to perform six or 12 or 18, some 20 biopsiew per session. i couldn't imagine doing that for other organs breast for example or kidney. if we see the tumor maybe we can eliminate the number of biopsies.

ongoing work on the campus here. when this work is altogether perfectly, you have this mri that's very bright. in this case healthy looking prostate and this little dark spot poking into this bright area trip zone we overlay the blue and red dot to make this

visible to the person doing the biopsy. and then we can direct the needle to that part. we can diagnose that tumor. and the next couple slides if we think we are overtreating this tumor, we have patients where we actually get confidence that

surveillance or neat -- no treatment is the best option. we can forego future biopsies we can see the tumor, we know where it is and we know future imaging is not going to go ahead and see a progression of that tumor. of the times it doesn't happen it doesn't progress.

so like this, this is the purpose of cancer. you have biopsies. one could imagine that the physician well intended trying to sample this with a random biopsy may have put one needle here or one needle there. it was in between the biopsy

samples. as a result, he had more confidence in that patient offering the survealance or treatment or other options. some of the publications that came from this were heavily criticized initially or over time as we amassed more patients

in our series. this one actually fell into the cover of our journal at this what this said was if we have an mri that can detect cancer, we have no level of suspicion it's high being the radiologist feels this is an aggressive tumor, biological active tumor and may

be one of the cancers. withcv techniques, this dark gray finds that more often in a random it's intuitive and makes sense but i have data to support this but what makes sense isn't always correct. the physician as i mentioned

before we could actually record locations and map these tumor locations. and have more confidence not to treat these tumor. we can follow them over a series of time and not require biopsies to follow them mostly. and then the clinicians who came

to us and said i would like help, i want to help, help me stop [indiscernible] once and for all if psa, if i'm invested in psa and many neurologists are, i know it's not cancer specific and we have the by see year after year, can this imaging stop me and]at)ut me

confidence and assurance i'm not hurting my patients. i believe many physicians are well intended when they embark on psa screening it's just hard emotions to get away from. when we analyze the data from our last series five years of data, and what these two graphs

show are this. if a patient came to us after the physician did multiple inive so say two sessions or three years or more it's proof performed well. we detect cancer or hidden and dissed in the traditional more importantly the mri again

said this is a you were to that's aggressive versus this is a tumor that's not aggressive, it works. it works well. and then in many cases, these high and suspicious tumor were discovered. but others argued that this

slide is probably the most important one because if we know that we are over diagnosing and particularly overtreating low great cancers or -- high grade cancers in this case -- was a pathologist to look at histological specimens and give a pattern to more aggressive

biology than less aggressive. it's not very aggressive and some circles of the academic world to be considered to move back into a -- and eight, nine and ten are considered high grade or lethal cancers, the question was does the mri mix the high grade cancers.

and so in these situations here whether 21 high grade cancers, a patient came in for biopsy the mri said this is the tumor. we blinded one clinician and he did a standard 12 core random blind biopsy. and then the patient in the same setting you turn on the mri

guidance and put a needle into what you felt was the cancer. and those patients more than half the time, 50% of the time for large high grade cancers the random biopsy missed it. [indiscernible].> and in cases where we have the mri technology, we actually we

were 100% detecting those tumors and these are the ones we do want to detect. so applications for physicians. not just screening. what about surveillance. we know that we overtreat. i think the physician and i think also the patient feels

more comfortable if there's a modality to interrogate the prostate with mr imaging and rule these out. i hope and believe that we'll have a larger active survealance. we have many younger patients cut into us today who say if i

had reassurance the tumor biology is not going to be addressive i'll engage in that. in doing so they looked at patients who met criteria of surveillance and image here and sure enough i would say probably somewhere between 40% of those patients had higher grade or

larger volume persuspected and able to use imaging. so they may have a disadvantage by pinning to be active surveillance. we're not sure but we'll see. very briefly, the treatment options. as an example this is an

individual who is 60 years of age at the time he came to us. 5% of the time -- imaging found people ask me when i give this lecture well how could this have been missed. needles that passed throughthevm prostate as dr. pinto mentioned it goes probably through the

eruthera -- a hundred percent of the so now the question is 60 years of age with gleaden 8 cancer do we go ahead and offer him treatment or not. it's not clear but we did. in cases like this with individuals we want to get that because of cancers.

prior negative biopsies. the tumors again are high grade this young man over here who is 68 yet healthy and very active in his life-style had two anniversaries one -- and he knew those dates. and then on the 7th year they pretty much on anesthesia i took

out 36 course of his prostate. that area right there was the area that was missed. for years we couldn't see these ma'am august fees -- mammographies have been around for a while -- it's a whole new world how we can improve whether we need to screen how we screen

how we use this technology how we treat how we can give drugs, follows these tumors, we can give medication and sampling. of course there was non-cancer in this case. finally this young man here had 15% of one core and he was adamant he wanted treatment.

it was not clear the options. trying to discuss the harms and benefits of each of the treatment options. a volume was this low that the cancers biology of this, again based on a random 12 core biopsy, he was able towq offer active surveillance, surgery

that could release the nerves while putting in therapy seeds sometimes a low grade an mri was performed to make sure there's no other tumors found this large dark spot among his prostate. this tumor biopsy of course came back with high grade cancer.

now those options have changed. the data that's collected has changed the treatment choices for this individual. the low grade is 5% below the low volume. the options are now gone. we know the true answer for this the true location and volume.

if he has surveillance at -- it's hard to find a patient to choose surveillance. maybe -- so survaluance was not an option for him. if he had surgery is mri -- says possibly it's in the nerve but you try to maintain quality of life.

you take [indiscernible] we would. the radiation is ineffective. ology to address it, randomized data from the bullet trial to suggest that you get radiation plus to spend on that person had surgery and the cancer was found to be -- spread

and that treatment option we believe is correct. so in summary, recent advances in prostate imaging and biopsy devices actually on this campus hey for the first time hint towards an opportunity to screen effectively. i'm always told mri misses so

many of these low grade low volume tumors. it may disregard those tumors and detect only ones that are aggressively potentially lethal. but there's so much work to be done. we have to figure out not just anecdotally how this works.

on a larger scale we can export this technology cumulatively, academically and beyond. my tam here, my collaborators. this is one of the -- received two years ago on this slide. of course only the clinicians in the white coat didn't know any better.

and of course i would not be here without the mentorship of -- who recruited me from hopkins at the time know what to do with my career. she gave me mentorship and gave me an opportunity for being what really is a very special place on this campus.

with that, introduce professor kay, a very special person -- le him say a few words about his story. [applause](paã± i'm let him go. he's got the podium. he can him his story. >> good afternoon, my name is

i want to say two things that i've been lucky twice. first that i was elected by dr. pinto and his team to take it, to be part ofhe pgram. and i am pretty sure that if i were not that lucky i wouldn't be standing here because my cancer was very aggressive.

and secondly, i wouldn't be standingn front of such a prominent audience of fine prominent physicians. so thank you very much for such an opportunity. >> stay up there for a couple seconds because i want you to explain to e audience what

happened. he had -- screening. i don't know if you clearly understood what that was. i think it was what was pointed i think you just got the box checked. i'm not sure if you were screened for cancer or you went

to your doctor. which was it. >> well, it was very simple. i never thought i was ill. i led a very active life. i played serious tennis, still playing today. i thought i was healthy. my daughter is medical

professional and she once said dad you have to check your psa test for just because of your able. age. i went to see my local physicians. he did blood test and he said you have a problem because your

psa level is high. i was fortunate because he said i don't know what your situation is but fortunately i live in the washington metropolitan area and he said i know dr. pinto and his team they have a very advanced program and i would ask maybe if you could get tested because dr.

pinto -- that's how it started. and i was very fortunate because my cancer, i was advised i was not a medical profession and it was aggressive. i don't know what happened to me. maybe i would be still alive but definitely not in such shape as

i am together. >> so his urologist was able to do a random biopsy and found, this is the case actually a or as part of the trials you successioned could we detect other tumors. one could argue what this type of low cancer even at your age

and we're probably unlicky to have found it. what we're trying to do on this campus is to get the patients have sudden terms which happened to be your one case. so the minuting that was performed in your tumor that was the spaws -- that was the most

aggressive biology butkh there were other low grade tumors and this is how it was worked out. >> most importantly i had no ij doctors ask you, do you have to get up at night to go to bathroom. no, never.

do you have any discomfort. no. i had absolutely noism tums to be honest with you and it was a big shock for me. anybody who has been through you couldn't imagine, you feel as if you are jailed or sentenced t something.

because you don't know what to do next. you practically, the rest of your life becomes meaningless over night. i'm not exaggerating anything i'm just sharing with you what i have been through. today the way he started

forgetting about it in the past only since my surgery here in this particular complex. become i/htjju)qq) myself very lucky. well i appreciate very much the opportunity to so you on the screen and -- not specialist i come to the conclusion this is

my immediate reactio that life and everything is about resources and funding. i have advanced decree in my and i finance large scale projects what i've been doing for 30 years. this is an element of today's discussion but at the same time

it's always about the cost. and whether money is spent effectively or not. my view is you cannot put the cost of the person is life. he at the end of the day if the pilot program which dr. pinto i believe very fecti by this presentation perform it can be

expanded. it would help to save a lot of maybe to save even money as you have presented before to reach the same result with lesser cost.zr because i'm a trained professional to count money and to see the best results or less

capital investment. apolize. so this is what this is all about. i believe at the end of the day each technology has to be tested but it has to be tested not only for effectiveness but cost effecteness well.

>> this is what people share on this campus to run the trials and see if it's effective clinically as expected. i wanted to thank you most. you asked me to find a patient it was challenging. we were scheduled during the snowstorm in january -- short

notice -- your assistant came over here. so i want to thank him very much. thank you. i'm not that young. >> i wanted to see at the time when every solid tumor was i -- you can go on-line.

i wanted to see because specialty brings imaging of prostate cancer -- have done so the ne pha is the to go ahead and workãƒwith -- in michigan to profile all these tumors. >> we have a repository in our branch for opportunities and

they are matched t those areas. again it's the patient that did this. without their help [indiscernible] >> >> i thought you were saying we shouldn't do psas or do a better job of interpreting that

data. because psa sting. my experience is it can be a very valuable test if you follow it over time. if you have three years of psa levels that seemed to be the slope that's going up and finally your primary care

physician says this has been going up for two or these years, it's not very high but it might make some sense for you to get >> ts is a very important i'll give you what we think about this. a rk from our lab one of our students just received

outstanding poster awards. ten posters are out standing. what we analyzed is the psa cut off for which the imagingoe maye a filter. and so we didn't get rid of it completely but we didn't get rid of it. but if psa is the entry points

where the next step is a random biopsy of which there are [indiscernible] in this country can be created a filtered and hold back all the biopsies and what we did over the past analysis for the past by years date points at a certain piece of cut off in trend there is a

point mris are being successful. we have to figure out on a larger scale how we can do this to make sure it was reproducible off this campus. so your point -- completely, i'm conflicted though because i am not so se if we shouldn't benefit it completely and move

on to something else whether it's different bio marker or in this case we're heavily vested in imaging. we get to a point where this is another trial on this campus where we're actually taking the cost down. you went through this.

a 45 minute stand with multiple parameters all the bells and whistle isown from a research standpoint. if we can modify that toã³m gg 15 minute or ten minute screen or other modalities and then use that as an entry point that may be subject -- all of this stuff

has to be worked out. it will take years to do this but it's worth the effort. >> [indiscernible]. >> [indiscernible] have not been affected by our screening tools and that's really two things. a direct exam and the psa test. this mri is something else can

below it out of the water and we see mortality drop. i'm not saying it's going to happen. i'm going to make an effort and going to help me make sure we do this directly but wouldn't that be fantastic. what with a feed the technology,

what is the combination of imaging and genomic profile. as i to my father, i'm staying a campus, we're going to try i think there's a reason for it because these lethal cancers, we're seen people coming at a very young age)c"x anecdotallypsa's a thousand -- they have tumors

reflected in, these young men have -- before screening. >> i hope it's not personal but do you have family history of this type of disease. >> no, i don't. the only thing i wanted to say about my family since this is

the question, it is not related to me because your wife isnot your relative. but my wife was based on screening diagnosed with colon cancer in 2005. she was born in 53. so she was diagnosed by doctor -- who is known in this,

in the medical community, i believe. and based on the screening,she was rushed to georgetownei the next day she was operated. and she had very little symptoms because she was diagnosed or advised by doctors about any other sptomatic discomfort

other than colon cancer. she was operating and survived to this day ten years. she's okay. and now based on family experiences and my wife's and mine, we believe that we didn't say it because of thescreening..h1< if she were not screened for

colon cancer, i believe that based on the severity of the case, it would be very very grave consequences for her. >> i just spent i think the question was -- was called -- for prostate cancer being use extensively overseas and not really in the united states --

high intensive ultrasound. it's a new form of oblative technology to destroy cancer in this case applied to prostate. i was invited to go overseas for the surgeons to give back persctive his. you don't fail in creating new devices to treat cancer.

behind that there are three other devices in development. the problem is who can use these. and so that's why as a surgeon that focuses actually is to filtered out those treatment. in particular what you're asking about -- you have to ask

yourself why that' the case. having data is still lacking on these -- and looking entirely overall disease improvement for cancer and also from the outcome and think wow. so basic technologies would resist the clinical trial in the states first and we're doing

that now we have a trial coming up here and we'll investigate >> up to now we've been talking about psa is a screening tool at the initial stages before we know thepepper has prostate how about your views, is it a useful tool after somebody's had radiation or other cancer

treatment. >> at least people [indiscernible] the funding of the cancer was it's been used effectively for post treatment assessment. for radiation there are what we call balance effect -- i don't want to speak out of turn and i

don't know exactly that's used to judge the efficacy of treatment foreradiation. but with surgical removal with the exception of few other sites that can make psa, we have very sensitive assays that helpsfh psa's down to zero. and that's not detecting cancer.

if there are a few cells left behind or denying cancer -- for those patients psa is very low value. historically it's below .2. it gets confidence to the clinician there's no return. >> listen on behalf of all of us we want to thank you.

>> thank you very much. >> sure. it's a stimulating topic of discussion, lots to think about. thank you very much.