Bone Scan Prostate Cancer

>> okay, we're going to get started and this is the clinical translational oncology course, in the government, you have to have an abbreviation so we call it traco for short and we've been doing this now for about 13 years and my name is terry moody and--we welcome our

fellows watchingot videocast. so i will like to thank our organizing committee, especially jonathan wiest, it costs money to do the videocast and generally this is monday afternoons four-six with two exceptions, today, because yesterday was labor day, a

holiday and the other monday holiday is october 12th, so we don't have class that day, we have it on tuesday october 13th. so what we try to do is we try to have a ph.d. such as myself lecture with a medical doctor, such as dr. choyke, to give us

different perspectives, we try to look at current treatments and see where the field is going. so every year we're changing things and adding different speakers and these are in there and one of the lecture system on epidemiology, there's types of

cancers, my specialty is lung cancer it's basically hidden from the immune system but using the immune choik point inhibitors, then the size of the lung is taken off so then using the inhibitors, you are immune, so the immune check point inhibitors are approved for

melanoma and there's clinical trials and other types of cancers which is quite promising for this area. so at nci, we not only do basic research, we do a lot of clinical trials and here in bethesda, we do phase one and phase two clinical trials nci

we have over a hundred clinical trials going on in building 10 at any given time. a lot in 2000, the small molecule inhibitors of receptor tyrosine kinases, so dr. simeonov will be talking about this and then in october we will talk about taupe i

isomer ace inhibitors. another way to treat with these and talk about that, prostate cancer, there's cancer of health disparities and african american, the women are especially more prone to [indiscernible] and then, for cancer, one theory is that any

cancer can have a number of stem cells. [indiscernible] for traditional chemo therapeutic drugs, another thing is that note only is it from mutations but also epigenetic phenomenon and the expression can be research by methylation and the dma and so

we have doctors to talk about that and then a new initiative by president obama in sequencing medicine and we've been doing this for many years whereby you do a genetic profile of the tumor and then this in turn dictates the treatment, so all of this for different things and

finally, the nano technology for this is a new way to deliver drugs in cancer patients and the hope is, it will make the drugs more effective and cause less [indiscernible]. so the course is open to anyone free of charge. you have to register at the web

site, registration closed last week so if any of you want to register, you just send me an e-mail and i can send you a form so can you enroll and then you can visit tumor boards and core facilities at the nci, so in late september, i'll have a list of various frequencies and you

you can go and see and this is all voluntary, if you don't want to do it, you don't have to but it gives you an opportunity to see how the patients are discussed with the treatment, and to see the core facilities at nci. we have a lot of them.

we're a big organization and we have a very big core. and then finally if you want to get a certification for the course, you have to take a final exam, a multiple guess exam, if it's questions, one question from each of the lectures and you take this online at the web

site and you have up to a month to take the exam and pass it. and then you will get your certificate. are there any questions on the organization of the course? okay, if not, then we will proceed, so cancer, you see each year we have over a million new

fagses in the u.s. and there's over a half a million deaths the big four are lung cancer, colon cancer, breast cancer and prostate cancer. each is at about 150,000, each year, but then when you look at mortality, these cancers cause about half of the mortality as

well, but the mortality is very differently distributed. lung cancer, extremely difficult to treat. so deliver, 90% of the people who get it will die from it, usually that's within a few years. colon cancer is better to treat,

but where we really need advances is in breast cancer and prostate cancer, especially breast cancer. you see we have 200,000 women getting it and about 20% or so actually die from it and what's going on is the mortality in breast cancer is actually

declining because the treatment's getting so good. we have antibodies to treat it, we have a limitation inhibitors to treat it. so there's lots of drugs that are available. we have lung cancer, we're just starting to find things that are

working and what we're find suggest tyrosine kinase inhibitors and those immune check point inhibitors so even greater promise. so it's lung cancer, the number of deaths is actually leveled off. and one of the primary reasons

for that is there's less smoking going on. but in other countries such as china they're smoking more. so in china, you would expect a big increase of lung cancer in about 20 years and so, the chinese have approached the u.s. to talk about the problem and

what can be done. so other cancers that kill 30,000 annually, pan krist at ace cancer, it's very difficult to treat. this will be a lecture later on in the course. another cancer that's very difficult to treat is ovarian

cancer, this will be lectured on by dr. enunciata, and brain cancer, bioblastoma is very difficult to treat. so there's still a lot of work to be done for the cancer and its treatment. so what are the cancer risks? well drinking alcohol

facilitatings liver cancer. so if you drink a little alcohol, that's good. if you drink too much, you can get liver cancer. that's that. asbestos, that causes mesothelioma of the lungs and asbestos is a material they

used, and even nih still has some asbestos in the walls as long as the walls are cover up and no one's dog construction on them, you're fine but if you see dust in the air, look out. diet so a lot of asians eat pickled food and as a result in china, they have high incidence

of stomach cancer. familial, some are genetic, such as breast cancer, bracka one or bracka two, high risk for cancer and similarly in colon cancer there are genetic compounds. hes come into play, especially in the female cancers, breast cancer, ovarian

cancer, estrow zygous gen is a hormone that can facilitate tumor growth. and men, you have projector own which can facilitate the growth of prostate cancer. a big problem now throughout the world is obesity. people are eating too much and

putting on weight and this leads to a higher risk of cancer, especially colon cancer. ionic radiation, such as the atomic bombs that were use indeed japan. many people died from leukemia initially from the radiation, tobacco.

people who smoke tobacco get lung cancer, oddly enough only one out of six tobacco smokers will actually die from lung cancer, many of them will die from other things, such as heart disease. uv radiation. what's happening in the world is

our ozone shield is getting depleted and as a result there's more uv radiation, this leads to melanoma and so in the u.s., melanoma's going up to other states especially florida and arizona. and then viruses, increase your risk of cancer especially hpv,

leading to cervical cancer and we will have a guest talking about this later on in the talk. so my specialty is lung cancer. we will use this as our first model. so with lung cancer we have 45 million current smokers but the good news is there's

45 million exsmokers in the u.s. now when you stop smoking your heart recovers very fast, but your risk for getting lung cancer, it takes about 10 years after you quit smoking to get back down to normal risk. so the carcinogens in your body, they build up and they at a

there for a while. and it's very difficult to quit smoking due to the nicotine addiction. nicotine is in the cigarette. and that's the primary component that made smoking a pleasurable experience. --another carcinogen for the

smoke is in the metabolite of nicotine. said another bad thing is the carbonate, it's varnish for your floors in your house and then there's heavy metal that could be very bad. such as chromium, arsenic, hide ravene is basically rocket fuel.

so the cigarettes have lots of bad things in them. but initially we have the car sin o jean, for the it, it gets metabolized by the enzyme, and then this carcinogen which has an epoxy in it, this leads to mutation and the genes for p53 and krase model are free

radicals quent wently mutated in lng cancer. so here you see benivate tiaras reason, it's an organic metabolite and then it gets hydrox lated by enzymes and it's actually for it right here and then interact with the gaunine. so you see the ben zohar tiaras

reason and you see the enzymes metrics tab o lieser first with the oxide and then the diol, and that interacts with the gonine and the dna, hopefully leading to the mutation. so the p450 enzymes activate the carcinogens by adding oxygen, but then phase two enzymes

convert the ox generated eighted carcinogen that is highly soluble as a water so it can be excreted. so the dna gets mutated at the rate of carcinogen activation and the detox and/or dma repair. so lung cancer fakes 20-25 years of smoking to ultimately lead to

cancer. and the tumor suppressor genes what it does is it has a check point of the cell cycle so in the s-phase, the dna replicates and the p53 keeps dna from being replicated. but when it gets damaged then you get greater replication of

the dna and the mutated dna in pular to the process of car sin o genesis. so generally p53 leads to program cell death so that the cells that are starting to get mutated will die. but when p53 is mutated, the mutated cells will then lift and

another thing that goes along with the p53 mutation is p21 expression and p21 when it's overexpressed it inhibits the gone-s transition, when it's mutated. then again, have you the cancer cells readily going into the s-phase of those.

so when p53 is active and it leads to apoptosis, gab, 45, dna repair and thrombows spondy lightis ensel which inhick thes angiogenesis of the tumors. in-- inhibits angiogenesis of the tumors. there's certain places where the p53 gets mutated such as axon

five, seven, and eight. and here we see a chart of percent point mutations and we see at position 157 and approximation 248, 214, there's lots of p53 model citizenitation in that position. there's p53 mutations. so when p53 is mutated then the

cells go from g-one to s-phase. and s-phase we get the dna replication ask the g-two phase, we have to go over a check poise and in the mphase the chromosomes get segregated and we go from an adult cell to two daughter cells. and in cancer research basically

we made lots of cell lines from tumors and these cell lines grow very rapidly and they go from adult to other cells within 24 hours. so every day, the cancer cell will duplicate. so p53 mediates the g-one to s-phase of the cell cycle.

dna damage increases t21 and p53, p53 drives program cell death or apoptosis, after dna damage. so when p53 gets mutated, it's very bad. for the cell cycle we have two major enzymes for partas participate in a trialing in

that. the cycle independent kinases and the psyche lynns. so in the cycle d-one, it's very important in growth and it's considered an onca gene. when we go from the g-one to s-phase, we have cdk-two, psychoindependent cain ace two

playing a prominent role but it's partner changes in the g-one phase, it's partner of cyclic ein the s-phase it's partner of cyclic a, then in the g-two phase, the partner for cyclic a-changes from cdhk-two to cdk-one and then when we go to the m-phase, the cdk-one

interacts with psyche lynn b, to process the seggregation of the chromosomes. so the psyche lynn department cain aces, p21, p57, p15, p16, p18, p19. so you see there's so many psyche lynns so involved and so many psyche lean involved and

this is a very important component in the tolls, the regulation of proliferation. the cancer cells are programmed to grow as fast as they can. so after 10 years of smoking, cells change and they become hypoplastic or metaplastic. after 15 years there's further

progression to displassia, all of these processes, hyper plassia, displassia are reversible if you stop smoking. but then after 20 years, a cluster of tumor cells were formed, a carcinoma, and then after 25 years, on a malignant cancer can form and this process

is not reversible. so for lung cancer it's thought that over those 25 year period, dozens of genes get mutated, but the question is, what's the driver mutation. what are the key mutations for the cancer verses what are the passenger mutations, you want to

focus on the driver mutations. so here we see, in a normal cell, everything's fine but then with hyper plassia, the cell number starts to increase. the cells are growing and then with displassia, the cells become disorganized, the cells will stack up on one another,

whereas normal cells have you content inhibition, with other mutations you get a carcinoma insitu. so lung cancer, it start in the lung, but then the cancer can metastasis to other organs and with lung cancer it undergoes metastasis to the liver,

lymphnodes, the brain, and the bone. especially the spinal cord. so here we see a normal lung and we see the villi,ot surface, and when you take a breath, you breathe in o-two and you exhale, co2. so this is what you're breathe

suggest all bbut in carcinogenesis we see we've lost the villi, there aren't many left, and we see the number of cells has increased dramatically. the bluer the nuclei of the cells, the pink is the cytoplasm.

so this is hyper mazia, now with displassia, we get disorganization of the cells. so now with adenoma you get a group of cells but if you have cancer at this stage and you know it, you just have a surgeon go in and remove that group of but if the cancer progresses to

an adcomo carc nome athis is malignant and this can undergo metastasis, all over your body. it's not the primary canc they're kills you, it's the metastasis. so here's another look. we have the normal cells. we start getting mutations such

as onca genes or the egf receptor and so the cancer get initiated and then growth factors promote the growth of these so then when you get enough growth, you get the malignant cells for me, shown in red and these cells in red can undergo metastasis to other

organs. so, with tumors so with the tumors they start in the carcinoma form and as the tumor gets bigger it needs to get access to oxygen is growth factors and so what it does, it has the host provide blood cells to the center of the tumor and

so these blood vessels dot part of angiogesis and deliver oxygen and nutrients so that the tumor can get bigger, and as it gets bigger, some cells can sluff off and the migration to other organs and metast. we mentioned p53, it's a tumor suppressor genes.

but you can also have p16 and the retinoblastoma gene, can you have other mutations and other phenomenon such as methylation of the genes and then with onca genes can you get amputations and psyche lynn d-one is in the cell cycle, so she mixes the onca gene when the egf receptor

gets activated and then, erb-two is also overexpressed especially in breast cancer. and there's an antibody herceptin, it's effective in treating women with erb two positive tumors. so the egf receptor and lung cancer gets mutated we found we

have tyroseen kinase inhibitors that are effective in lung cancers. so these show you then, the receptor tyroseen kinases, the egf receptor. over a thousand amino acids and it binds shown in green and in the yellow these are structural

domains, with the rich domain. and and when it's mutated, it dimerizes and the on the intracellular side and this phosphorylates the protein substrate starting the growth cycle. so it's similar to the egf receptor, except that it binds

insulin, not epidermal growth factor. this is an egf receptor is a monomerand then some of the tyrosine kinase receptors have the immunoglobulin domains such as ted egf receptor and the veg f receptor. and this is important in

angiogenesis. so in terms of ligands, the egf receptor, or it's clled the erb one receptor or ehrr one receptor has many ligands such as egf. the lung cancer cells i work with, they especially make tgf alpha, transform being low

factor alpha which binds to the egf receptor, and curiously there's also erb two receptors on lung cancer cells. or her-two new, but there's no ligand for this, but the way it gets phosphorylated is the egf receptor can perform homodimers for itself and form a

heterodimer with the phosphorrulation of this too. so the egf receptor, it's big, 621 amino acids extra cellular domains, one and three, climb the growth factor and remains two and four are rich in amino acids. and there a one transmembrane

domain and 24 amino acids and then a 541 amino acid intracellular domain as tyrosine kinase activity. and in particular, the lysine binds atp. and the afp is transferred to tyrovene amino acids on protein substrate.

and in addition the tyrovene phosphorylate itself and 1086, 1148, and 1174. so egf receptor, it's been a big thing in the lung cancer in the years and all these have been developed with drugs. and egherk f finds those high affinity as cgf alpha and can

you couple the tgf alpha to cytotoxic such as the pseudotoxins 38, and it will kill the cancer cell. so this is work that's done by ira paston of nci and when you had egf, you see the egf receptor strongly phosphorylated, is that 180

kilodaltons and also you see substrates like foster nursed focused on lipase gam afrons 148, phosphorylated and here's pi-three kinase getting those phosphorylated and that's reversed by the tyrosine kinase inhibitors, defit nib or erlot nib, so these kinase inhibitors,

they basically hit into the binding site so that the atp can't get in and if the atp can't get into the egf receptor, the substrate gets phosphorylated. so the lung cancer, it was found that certain amino acids get phosphorylated, get mutated such

as the leucine 858 gets converted to an r-generateddine or the glue marious seen gets converted to a cystine, and this then increases the affinity. they block the atp binding sites; so here you see the gene, actually the schematic of the egf receptors and the kinase

domain and you can get mutations and amino acids 858 or 717. and this effects the sensitivity then to erlot nib, so if you're doing molecular medicine, you go into the tumor, you do a genetic analysis; if you see that the 17-19 position is mutated or the 858 position is mutated, you

know defit nib or erlot nib are going to work in that patient. so this is what molecular medicine is all about. so the egf receptor, we mentioned that there's what's called signal transduction pathways by which it stimulates growth, and ultimately what

happens is, this protein called erquan two gets phosphorylated and goes into the nucleus, and turns on expression of certain genes such as c-ph os, and [indiscernible] which trigger the growth. so the tgf alpha binds to the receptor, the tyrosine

phosphorylate itself, or hr-two and it interacts with the adaptive protein and goes through the ras, raf, halfway, to stimulate growth. and then the egf receptor, we have mutations in about 15% of the lung cancer patient so k-rase model is an onca gene

when it gets turned on, it stimulates growth. so krase model gets mutated especially at codon twel and in frederick there's a big research program initiative using ras as a molecular target so they're coming up with new ways to effect you haditated rase model

to inhibit cancer growth. there's the kinase called raf, it gets mutated, of 600 to a glutea mate, the patient's become responsive to a tyroseen kinase inhick thor so about 60% of the melanoma patients get mutated-ras and they respond to the drug klx 40-32.

so for bras are considered driver mutations in cancer. and then mck is a protein cain ace. it will phosphorylate erk, and there are mck, inhibitors in the clinic, there are and as we mentioned erk goes into the nucleus causing the expression

nuclear onca gene such as foster nursed, or myk. so here's a cortoon where we see the egf bind causes the homodimerrization to form. activating raf, which activates raf, which activates myk, which goes into the nucleus and alters the gene expression leading to

increased proliferation. and this is the cartoon, showing the crystal structure, of the and when i first saw this five years ago, it sort of blue my mind. but here you see a monomer, we have domains one which binds egf in domain three, two and four

are the cystine rich domain. and they dimerize and form inactive dimer, and then they sort of twist around another when egf five causing a confirmation change turning on the tyrosine kinase activity. and so when it gets activated, the mtor pathway emulating

survival so the cancer cells don't want to undergo apoptosis, they want to stop apopitose and i guess continue to grow. and and so the apoptosis goes through pi-three kinase and through akt, and then through mtor, and pi-three cain ace can be mutated in breast cancer,

bioblast homa and results in a gain of enzymatic activity so this will increase survival with the pi-three kinase gets p-10 is an enzyme which inhibits the activation of the pi-three kinase, but p-10 is mutated in about 15% of the breast cancer ps and when p-10 is

inhibited then there's more tyrovene phosphorylation, there's more survival. and akt, there's really very little mutation of akt, people are trying to develop drugs for akt, and mtor to use in terms of cancer treatment, but there's a long ways to go.

and this one's a little hard to see, but this is sort of one of the protocols that was present here at nci for treating lung cancer patients whereby you biopsy the tumor and if it has an egf receptor mutation then the patient gets treated with erlot nib, if it doesn't have an

egf mutation, we look for the myk mutation fist it has that then use the myk inhibitor to treat the patient t. doesn't have a rase model, raf, or myk mutation then you look for the ekt mutation if you pass that mutation, you use the kinase inhibitorot patient.

if it doesn't, you look for erb two mutations but has it has two mutation its gets treated with hepatitis eat nib and then look for you the mutation fist it has that you treat with the tyroseen kinase inhibitors and if it doesn't, you just sort of progress.

and use traditional chemo therapyot patient. so this is the area of molecar medicine i was discussing, you look for mutation, and if you find a museumitation that, in turn dictates that the treatment of the patient. but initially for the inhibitors

they worked really good and then after a year they were not working good on the patients and it was because they had undergone further mutations on the egf receptors and in half the patients there is this mutation of the egf receptor and so, erlot nib and and defit nib

don't any longer work so you have to come up with something else for the patient so the chemists are synthesizing second generation, egf recept inhick thors, third generation egf receptor inhibitors and it goes on and on, so the point is, cancer is a moving target.

you get something that works, that's great but you gotta keep your eye out because the cancer could then mutate into something else is then you have to basically start over again. so another example for tyrosine kinase inhibitors are cml patients, these are patients

with leukemia. so you get excess proliferation of white cells in the blood and it was found that glevak, was the first inhibitor that proved useful in patients and with cml patients they don't have mutations they have a translocation.

and segments of chromosome nine and 22, get fused generates wag's called a vcrg, and this gene is very active. so here we see on chromosome 22 and chromosome nine there's a bank point and then a and then you get a protein, and the biologists were able to

determine this because when you look at the chromosomes, you see if there's translocation, chromosome shine gets bigger and chromosome 22, which has bcr-abled gets smaller. so this was before molecular medicine and all the sequence analysis of the human genome was

known. and so, the toxicity of the glevek, was nausea, vomiting, edema and rash, something life threatening and after a year, 53 of 54 patients responded and over a five year period, 89% of the patients had no evidence of cancer whatsoever.

and here again we see that the grieve gleevec binds to the atp of the tyrosine kinase. but after years they started finding some resistance again and they found that the mutation was a point mutation, the position 315 was replaced by a luseen, so then second

generation, tyrosine kinase inhibitors were developed so again it's evidence of the cancer mutating into something else. so the cancers are very smart, they want to keep growing. and the scientists we think we're smart but we have to keep

working. because the cancer can outsmart us. so cml we mentioned ehre mat nib, andy for breast cancer we have herceptin which is a monoclonal antibody, and lapp a tanib, and for melanoma we have b-raff, and plx 4032 is

effective. this gastrointestinal stromal tissue has one called c-kit, but it was found that imatin increase in body works and the sunitinib, works and the then we have gefitinib, and erlot nib as tyrosine inhibitors. and now how are we going to

prevent cancer for f-reporting developing. so a real big area in cancer and chemo prevention, how can we stop the cancer from forming? and one of the things i learned when i moved to maryland is check your house for radon, radon causes lung cancer.

a lot of the rocks in this area have radon in them. so i moved out to the country, a house on a hill and when i went to sell the house, they said, we can't sell it because have you too much radon in your basement, have you so much radon it would be the equivalent of smoking two

packs of cigarettes a day had you lived down there. well we lived on the main floor so that was fortunate but then to sell the house, we had to put in a pump and the pump basically just puts air in the basement so that the radon gets flushed out. you want to check your house for

asbestos, we mentioned before, that asbestos in the wall can cause mesothelioma of the lungs. and unfortunately, even at nih, many of the buildings, the older buildings still have this asbestos in the walls. you want to check your community system for water, if you want to

drink good water, you don't want to breathe polluted air, it was a graduate student in cal-tech in los angeles, so i lived there for five years and every day around 1:00 o'clock my lungs would start hurting from the ozone. the ozone would come through

pasadena every day around 1:00 o'clock and you feel your lungs burning up. they said for every two years you live indeed pasadena, you would lose one yore of your life. i don't know if that's true or not but i said, well, i'm going

to go to nih when i graduate. and d. c.'s not that bad. we have a lot of wins. it blow its out to the ocean. so protect your skin. so we mentioned about the uv exposure, you don't want to get melanoma, so when i go outside, and i like to garden, so i put

on sunscreen so i tan and not burn. you don't want to breathe smoke and can lead to lung cancer and you want to exercise this and exercising, i do a lot of bicycling and this saturday i'm supposed to right in what's called the civil war century, a

hundred miles of riding through the countryside of maryland and pennsylvania. and pesticides these can lead to prostate cancer and eat lots of fruits and vegetables and they have antioxidants. we mentioned the chemicals have to be oxidized to become

carcinogens. so if you have antioxidants, that's good. you want to reduce red meet comsumption, they have omega three fatty acids, then there's white foods, drink whole in moderation, avoid unnecessary x-rays and we reduce infections,

we mentioned before that cervical cancer comes from the hpv virus. and finally, we have some preferences and that's the conclusion of my lecture. so there are any questions. >> [indiscernible] >> they they generally make the

patient feel better, but they don't really cure the cancer. they--yes, you have to keep taking it once you get on the drug. but in contrast now with the immune check point inhibitors, they actually improve survival, so that's what you're really

looking for is the reduction in tumor size but as well, a dramatic increase in survival. yes? >> [indiscernible]. >> not yet but that's a good idea, so in general when you test the new drugs, the fda mandates you have to test each

drug separately and then once they're proven safe separately then it's possible to combine them. but what's going on basically, is if people when they become resistent to the tyrosine kinase inhibitors, now they're trying to put these patients on the

ine check point inhibitors. okay, we have pete. you want to load your presentation or just use the one you sent me. okay. >> okay, so this is pete choyke, he is the director of the molecular imaging program.

he got his md from jefferson medical college, he did his residency at the new haven hospital and following the internship at pennsylvania, he joined the faculty of george down and then in 2004, we were very fortunate to recruit him here.

pete? >> thank you, terry. i'm still trying to recover from your hundred mile ride on saturday. that's great. well, let's see, my name's pete choyke, oom a radiologyst in the national cancer institute and

what what i'd like to do today, is sort of give you a virtual tour of a radiology department, what's in it, what kind of equipment, what works, what are new developments and how we image cancer. so as can you see, there are a variety of different machines

that kind of look the same, they all have an area where the imaging takes place and a bed or a gauntry where the patient sits, so we'll talk about--first,--recently approved by medicare ct scans for lung cancer in smokers, and so that's a way to detect cancer at its

earliest time before it spread and as obvious implications for survival. then, once a cancer is detected by other means, an important role of images is staging and staging divide into's three categories the t, and m parts of cancer, so t meaning the local

parts or topology of the cancer. and n-meaning whether there's nodal involvement and m-meaning whether there's distant the tnm classification that's used around the world and imaging is very important to understanding how far the cancer has grown or metastasize.

then once all that's done, the patient is treated some way and the imaging is usinged serally to see if they're growing responding or recurring. and then of course in the same vain as recurrence, that is even after the patient's been treated, they are--and the

cancer apparently goes away, patients are brought back periodically, so that if the tumor does recur as a later time tcan be treated propertily so has it come back? and sometimes imaging is just obtained to give an overall estimation of what the patient's

progressinoseis is, whether the amount ofumor is so great that there's no real reason to pursue therapy or whether there's a modest amount of cancer that warrants therapies. so that's prognosis, the main devices that i'm going to talk about today are computer

tomography or ct, magnetic resonance imaging, or mri, result rasound, single photon tissue and macrophagessography, and posatron omission tomography or pet and we'll say a few words at the end about optimal imaging which is not a traditional imaging technique found in most

radiology departments. so as i alluded to in the beginning; if you--field functions were to quiz you on which scanner was which, i would forgive you for not knowing which one is which because superficially they all look the same and frankly as a board

certified radiology, sometimes i don't even know what the machine is until i look at the very tight details of what's going on. the exception isultrasoundltrasound over here on the right as a unique appearance, and we'll talk a little bit about that, but the basic

architecture of the imaging device found in a modern imaging department, looked very similar to each other and we're not going to talk about plain old x-rays because we assume that you guys have either intersected with that or it's so obvious that you wouldn't need to and in

any case, conventional x-rays really play a relatively minor role in the management of patients with cancer. we're mainly doing cross sectional imaging. dealing with taking backfield or sageinal or colonal images of the body.

so this is a perfect example, this is a ct scan of a patient with lung cancer and you can see, the tumor here behind the tumor or distal to the tumor there's inflammation that won't heal because it's blocked by this tumor. so it's kind of a blocked

infection that just persists over time. and there's some volume loss in the lung so you learn a great deal just from a simple single place through the chest. so this is the normal size lung but can you see a tiny moduleot other side indicate thanksgiving

cancer may have metastasized to the other side. these are otherwise very difficult to see things the way this image is windowed. about that. so, ct i'm going to talk about first because it's really the most important of the techniques

we use in the department. it has advantages of being very widely available. there's minimal preparation, so this means--the patient shouldn't eat anything before coming to the department for ct and then they'll be asked to drink contrast, oral contrast to

pacify the bowel, but other than that there's minimal preparation, it's very rapid, the machines we have now in the radiology department can scan from essentially the lower feph to the pelvis in two-three seconds, so a single hold all the way through, the entry is so

fast that the engineers have to install a break in it to slow the patient down at the end otherwise they found in dummies that the dummy slid off the table due to the deceleration, so we now have a very nice breaking system in this, but it's an extremely rapid--i mean

incredibly rapid with understands of images in just a second. and then, it's very high resolution and it's relatively inexpensive. and that's largely due to the through put, you can obviously do patient's very rapidly with

these machines and as a result, even though it costs over a million dollars to buy a machine, you can see how it could be paid for rapidly. there are a number of disadvantages to ct. most obvious one is that it uses radiation.

it awive requires intranslational research venous contrast media which can have allergic reactions, it's very, very unusual but it can happen. and in patients who already have some renal damage, the automated contrast media that we use for ct can cause further damage, so

that's a risk in patient who is have renal dysfunction, and ultimately one of the disadvantages of ct, it only provides with an atom, not anything about the function of what's going on, just the structure. now how does this work?

and this applies also to plain radiography but the--the basic set up is that have you a power source, a wire, goes to a coil that burns off electrons, so that's the cathode, and it's attracted to the anode which is positively charged so these electrons go with quite a degree

of force into this target and you can see that it's an angled target and it's just like any collision experi. there's an interaction of these electrons with the target, and x-rays come off in multiple directions. and those x-rays are directed

towards the patient. now, a very important aspect of this is if you just let this anode and cathode behave like that, you would get x-rays all over the place. so one of the important things is to put a columnator here to guide the x-rays in a certain

direction, so it blocks all the unwanted directions and just has the direction you want toward the patient. so the patient lies on the table, the gauntry, being a part of the table that's inside the instrument, in this case, the ct ask this x-rays go through the

patient and tue a ring of detectors that are complete plea circumtrenteral around the patient. and as you can imagine, from this idea of ct projection or filtered back projection, as you take multipws of these four tubes, you will get

different profiles, depending on where you are. so, at one point, at this diagonal, you will see three bumps, at this perpen dickular, two as you go this way and three as you go this way and two as you go up and down and as do you this more and more, you will

begin to recognize the four tubes that are in there and this is called r back projection. now there are many, many sophisticated image processing alegorithmses that clean up this image significantly. but this is the basis for the

imaging, one of the things you can do is something called foray transforms and you can look at these wave forms and perform a forforray transform and you that can clean up the image significantly. so as we get away from the cartoon and towards an actual

model of a ct scanner, you'll find the ct source here with the x-ray fan coming down to the patient against the detector array and then data acquisition systems around this because the amount of data pouring out of this is so fast that you have to have your acquisition systems

right there to kacct --tocapture it all. now we talk about the spiral ct and that's because the acquisition is occurring as the patient is moving on this table. and so, in a--in space, it prescribes a spiral around the so the extra tube is moving, the patient is moving so you get

this kind of coil like appearance or spiral like appearance and that's important because we think about ct scans of these individual slices, that's what we look at, but that's not really what they are, they're really volumes of data and then there are

retrospectively cut in the way that we see them, so we obtain it as a volume and then we cut it. well, it that's important because now we can cut it in any plane that we want to. it's not just axial, it can be this way, sageital or this way

colonial and that can be important for different cancers to look at better so this is an example of how that volumeet rick ct can be used. to rook at these the way you look at things but then i'll see something for instance in the kidneys that bother me and i

woud like to take another look at it, you know like what is this little cystic area and i'll put it in the colonal plain quickly and you can reassure yf that it's really nothing. it's a normal variant. now if have you a question about

what's going on in the bones, this sageital is a way to look at the spine because you see how each of these is a bind and whether there's any compression fact fracture or evidence of metastasis, so you can see how it's use toful have this volume of ct.

now one thing we'll talk about in a minute is how to reduce the amount of radiation exposure that patients receive during the ct. now keep in mind is over for two or three seconds and it's going over the whole body and na's not a trivial exposure, so what

people have figured out there is that the body has different densities at different parts so in the lungs there's relatively lower density than in the belly and as you thin out to the pelvis there's less dense its over all and so can you modulate the amount of x-ray for the body

part so that the shoulders where there's lots of bone and soft tissue might get a lot of relatively high amount of x-ray, the lungs could be dramatically dose reduced. and this can be adjusted to the size of the patient and more or less realtime as the patients

are on the scanner. so this gives--brings us to the issue of radiation. so this issue came to the foreabout six or seven years ago in a tragic case on west coast, it was a young patient for betting a scan for trauma of the head and the scan was set up the

child got the ct, the child was not teabtive to what was going on and it turned out for whatever button the technologyst push that the scan kept going and going and going and it was several minutes before they realize that the scan was going on and the child had a radiation

burn on their scalp and and it was widely disseminated. now it's--you know social media, it was just, it spread like wildfire within minutes ry radiology department in the united states new about this tragedy. the child by the way has now

been followed for six or seven years, nothing has happened, but, i mean obviously, everybody at that hospital is going to hold their breath for the rest of this kid's life because of what could happen. but it caused an earthquake in the manufactures.

i mean how is it that you could keep a ct scan going under any circumstances, for three or four minutes. it just--why do you even have that feature so that was eliminated. but people started to think, really are we doing everything

we can to reduce the amount of radiation these scanners put out. for years we were thinking about doing a precontrast scan, an early post contrast scan, a late post contrast scan, delayed post contrafort scan. radiation didn't enter into the

picture. well, now maybe we should pay attention to this and it's quite true, now, that--now that engineers have gotten in on the game, we can dramatically improve the sensitivity of the detectors, we can use the modulation of the body size,

we--there are all kinds of tricks of using dual energy, low energy and high energy beam to reduce the amount of overall radio activity and so, we have--sorry, we've--we've been able to lower the amount of energy of the x-rays, the detectives will be more

sensitive, there's better reconstruction algorithms, there are images that can be calculated from other images so before we had to take a scan, before contrast, to see a noncontrast scan. now we can subtract out the iodine and say this is what a

precontrast scan would have looked like. so it's completely simulated but the patient doesn't have to have that second scan. so as a result there, there have been dramatic reductions in the amount of radiation. the second thing i want to talk

about, is this automated contrast media, it's extremely useful. this is a precontrast scan ask this is a post contrast scan, you clearly make out this lesion and here can you not only make it out but characterize it as a cyst and of no consequence.

so, this is an extremely useful part of what we do. so in any ct scanner not only what you'll find is the ct itself but also a pump that injects the contrast and flushs it with the second syringe that flushs saline through it and typically will use some kind of

automated contrast media. now one of the great inventions of the 20th century in my estimation was the invention of nonionic contrast, when i first got started, the contrast was ionic and it would be two or three times a week, there would be a major allergic reaction to

automated contrast, in the late 1980s, people developed nonionic contrast tcame out of norway, and it revolutionized the amount of allergic reactions so that in the current department, using automated contrast, it's maybe once a year that we have an ox ledgerric reaction.

so it's very, very powerful. and the other concept that i want to leave you with on ct is how to window a ct. so, one of the powers of ct, is that you can take the same image and then window it in different ways to get different information.

so for instance, you can get information from the heart on this window and the lungs on with window and we could do another window that would tell us about the bones and and dramaticsly more information by playing with that. so what we talk about was

windowing, is how broad the gray scale is, so this image is made up of potentially of different gray scales from white to black. if you limit the window, should this--so that the darkest--i should say the lightest thing on this, image will be sort of light gray, and the darkest will

be dark gray. so you get a very dark image than if you have a window like this, that extends all the way along the scale from very light gray to black. so i think the arrows may be a little confusing, they should be reversed so with they would like

to move on to the second modality which is mri, magnetic resonance imaging, a very powerful technique. here i'm illustrating a prostrate mr i, and this is the prostate gland and in the interior part, the consumer and you can see the path specimen,

where can you see, how well, the tumor was depicted by the mri, although there are two smaller tumors that are not seenot mri, these are inconsequencial, very low grade area and wouldn't have required treatment. so mri has some distinct advantages.

unlike ct there, 's no radiation involved no ionizing radiation, it's directly multiplanar, you can scan in any direction that you want and the most important thing is that it has multiple contrast types. so we talk in terms of t-one waiting, t-two waiting,

diffusion weighting, contrast enhance, spectroscopy, all of these provide different windows into the pathology that's inside the body and so it becomes multiparametric, and you don't look at things just simply because of their x-ray attenuation, you look at them

through their mr-characteristics. disadvantages, well it's considerably slower than ct, we said we could get through the whole body in-23 seconds, not true with mri, it takes 30 minutes, some of the mris can be longer.

the machine is more expensive, the machine is slower, so the per scan cost will be higher so it's more expensive. it doesn't depict things like calcifications which is clearly a limitation for things like kidney stones. and there are some safety

issues, very different than ct. the biggest ones are that ordinary objects, outside of magnetic scanner are harmless but inside the mri can become a lethal projectile. so we train very heavily on safety with mri, and then there are a number of incompatible

devices like pace maker exps cochlear implants that can't function or will be disrupted by being in a strong magnetic field. so we're going to do all of mr physics in about five minutes. some would say that's all you need so this is going to be a

rush job, but we'll see how it goes, what's the principle behind mri, i hope after these five minutes you'll agree with me that it's amazing that it worked, but here's how it works. you will have protoons, mainly associate wide water molecules, h20 so there are two protons per

every water molecule where they're fill wide port and lots prove tons and as you sit here, they're wandering all over space in terms of their spin. t directed randomly. now if you put them in a magnetic field, they will align with the magnetic field, they'll

either go in the direction of the magnetic field or the opposite direction of the magnetic field but either way, they're aligned with the magnetic field. now, the--one of the pieces of magic is at a certain magnetic field, they have what's known as

resonance frequency, so they're spinning around their access, not just alined like a soldier, they're actually spinning. and the frequency that they're spin around is a resonance frequency and if you hit them with a radio frequency wave at that frequency, the resonance

frequency, can you get them to do things. can you get them to do tricks, like, deviate from their axis into a another plane, so can you get them to rotate all the way down to being in the opposite direction. energy is absorbed.

good. because when energ seabsorbed, it can be--energy is absorbed and when it is absorbed it can be retrieved at a later time. so when you turn it off at the frequency, turn it off as the spin starts to return back they give off radio frequency waves

at the resonance prequency, so here we are applying to resonance frequency, where shifting the spins down to another plane and as it relaxs, it's going to give back signals and this is the complex radio frequency pulses that are applied during an average mr

sequence. so we're going to stop there with the electron and the spin and the protons because it's going to get--we don't really want to go down that street. we just want to know where it all comes from. amazingly enough from that

property that i just described, a couple nobel prizes are in there, but from that, we have--are able to generate images. one of the tricks is to apply what's known as magnetic craniums across the body in sequence and when you do that,

you change the magnetic field at each point in the body. which means you change the resonance frequency at each point which means that when you excite with one resonance frequency, you're only exciting a certain part of the body. not everything.

so the trick is to apply these magnetic gradient increasing in strength as you go through and you'll scan different parts of the body by doing that. you go steer what you're able to image just by applying a magnetic field to the patient. very cool.

comprehend. now how do we get this all to actually work? so what we have in an mri magnet this, is a cross section is starting from the--have you a part that the patient experiences, sort of a plastic tube, and inside that, are the

coils, that will not only generate, the--the radio frequence that's we're talking about, but also receive the signal that's coming back, so, you have antennas that not only send out the signal but also receive. so this is the--what's in this,

called the rf body coil. so that's sitting right there. right behind that, are the gradient coils. so remember i said to get spacial recognition, you need to apply these gradients, magnetic gradient and so that's what comes next and then there's an

insulator and then, there's this phase, which is super cool, to near absolute zero, and it has titanium wire in it and through that, the magnet is charged up with a huge amount of energy so when a magnet is commissioned they come in with a generator and essentially apply a huge

amount of energy to the super conducting wires. they fire up and they're an electromagnet, so they generate a huge magnetic field that's steady, like a rock and we have what's called the cold head which allows that liquid helium to surround this wire so that,

we're condistantly at absolute zero in the outer layers of this magnet so we can keep it under vacuum with thermal insulation and keep it super cooled and keep the super conduct ant and thattate basic anatomy. so once you put all the covers oit--it looks like there and it

looks very much like the ct scan, you know with the pantly and the table and the injector, now, there's another thing here, the ear protection, because this is very loud. this process is very loud, you say where's the noise coming from.

well, on this, the application of the gradient creates movement, just a little bit of movement in the coils that we're talking about and that movement causes a vibration noise that's transmitted into the gauntry and it's very loud, so we have to have here protection.

oorktd thing you always see in a ct nan mri is it differentiates it from a ct, so when i walk interest a room, trying to decide is that a ct or an mri, you have to look here, something going through the roof, that's the mri, that's the quench pipe. so here's the problem, let's

suppose that there's a short in that wire, that we just charged up with a lot of energy that makes a magnetic field. this is short. well, it--it burns, it creates heat, it vaporizeslet liquid helium around it and all of a sudden have you this release of

liquid helium converted to gaseous helium and you have to get rid of that quickly. otherwise, your room will fill up with liquid helium and not oxygen or air and that means people in the room will suffocate. and i'm not kidding, that can

happen. so what we do in every installation and have an emergency quench pipe that goes to the outside and it--it's designed as a pipe basically designed to take the helium, gas helium and vent it outside very rapidly.

so it doesn't accumulate in the room. now a few words about mr safety, now there are few things that be aed to high speed mris, so key, scissors, any kind of tools, and of course, mops and buckets can be sucked into a magnet and people forget that

even though the lights are off in an mri scanner, you know, everything's quiet, the magnet is still on, always on, 24/7, 365 so if you walk into an mri, room, with metallic objects, they will go right into the scanner. if a patient happens to be

there, you can--it could be a big problem, in fact another tragic case that happened that happened 10 or 15 years ago was a patient who was a young patient again. who was getting--needed to be sedated for the mri, and they were there with

an anesthesiologist and the anesthesiologist realized that the oxygen in the tube he had in the room had run out. and he was very worried about the kid not having oxygen, so he yelled out i need oxygen, i need oxygen. some helpful person came in with

an oxygen tank that was not mr compatible. and it killed the child as a projectile, it was a torpedo and it flew into that, so safety is incredibly important and in fact, there's actual partly because of that, we design our mr facilities to have various

zones so, these are safety zones, zone four is where the magnet is, zone three is the control room for the magnet so you can't even get into the control room unless you're checked or an employee. zone two, is where the patient is dressed, this is where the

questioning takes place, do have you metal objects, do have you implants, pace makers, et cetera and then there's recepton where it's considered a saist zone, but we--you see that you don't get access to the mri directly. you have to go through a serious of checks to make sure that

everything is cool before you go in there. otherwise stuff like this can happen, like the buffer for the floor and a tool chest just gets there's the oxygen--not the one that caused the damage but--so, finally a word about mr contrast.

so here's a tumor that's lighting up in the liver and the only way you could see it was with the contrast and this is gatta lynnium and it turns out that gatta lynnium is a toxic element and for instance chloride into somebody, you will--you'll cause a lot of

problems, but if you attach it to accumulate such as one of the ones shown here, you can very safely get the property you want that is relaxing, the magnetic field, without the damage that free--now this is very topical and is something that's going on right now, there are a number of

approved agents and they have different chemical properties, but this is quite important. thermodynamic ability complex, that's basically how tightly is that gatta lynnium bound to that, what would it take to get it off. so a high number means you have

to put a lot of energy to put it a low number means that it's not that hard to get it off and these are measured in log scale so between this agent and this agent, there's literally 10 to the 10 fold difference in the accumulating ability of these two compounds.

10 to the 10th. well that's interesting. a few years ago, it was reported that patients who had had multiple exposures to gada lynnium and who had renal failure so they weren't clearing the gada lynnium as fast as other people were getting these

kind of rashes and strictures in their hand, they couldn't move their hand and when it was disciplinaryopsied it wassa kindave systemic sclerosis, and it was tracked to free gada lynnium that was coming off of these, but the ones at the lower end of the term o dynamic scale.

so it was first noticed in denmark, may of 2006, 25 cases of the nose neffergenic systemic sclerose and i guess it was largely traced to it form of gatta lynnium contrast agents. and there were a number of other reports in 2006, and ultimately 200 cases were reported.

but it became quite clear if you switched to another gada lynnium, one with a higher stability, you could eliminate this side effect and by 2013, there were no cases reported and it's something that is something we screen for, we look for renal function.

we use agents with high thermodynamic stability and this is just an example, just to show you on this bone scan how much damage there is throughout the entire body of this, it's very toxic and although patients with normal renal function excrete gadda lynnium normally, patients

with abnormal renal function may take weeks and leading to fairly high concentrations in this, and fibrosis is a reaction to that free gat gadda lynnium, so those are the risk factor but as i said this is really pretty much eliminated as we got rid of these--of these kinds of scans

and only reserve these--only reserve these agents for normal renal function. but very recently, people have been notice tag patient with us renal dysfunction have this brightened in their--in the dentate nucleus and basal ganglia of their brain and when

they look back they see those patients who received multiple doses of gadda lynnium. now there are no known side effects from dagolynnium, but one can argue this is not a good thing. so woo have list of agents and it's quite clear that we need to

start moving up this thermodynamic stability to the very best. so it's never been reported with this agent or this agent, and these are the ones with the high term o dynamic stability. so this is another example. let's shift over to ultrasound.

again ultrasound is something that's cool because no radiation, it's realtime, inpecks en--strategiesive, quick, no prep, no injection. it has disadvantages, it very much dependot expertise of the person dog the scan. ct as long as can you push the

right set of buttons you'll get a beautiful image. ultrasound not true. you need expertise, took me at least a year to get good at ultrasound. so, another part of ultrasound is it's rike a flashlight. you only see where you shine the

flashlight. so if you don't look at a certain area, you won't see it unlike ct, it's like lighting up the whole room. difficult to quantify, and there's limited access to some tissues like the lungs, the air in the lungs just reflect sound,

you'll never see it. the bone surrounding the brain prevents sound from getting there. you just have limitations from where can you use it. so the basics are pretty self-evident. have you a transmitter, in, it

reflects off something. and you hear it back. now, the medium through which it goes can change the pede of the sound and you can measure that as a change in the time that you--that you hear the echo. so, in a slow tissue like whort, it will take longer to get back

verses condensed tissue like muscle where the sound will return faster, so can you get a characterization of tissue based on the speed of sound. when you send sound out into the body, can you get various things one is attenuation, for instance the skull would attenuate the

sound it'll never bet deeper, the sound can be absorbed witout any reflection, that's unusual, it can be reflected. that's what we depend on. it can be scattered or refracted. or even defracted. so there are a number of

artifacts but artifacts this is a typical ultrasound in a patient with colon cancer and you can see the metastasis and they look brighter because they're reflecting the sound better than the normal liver tissue. so, the anatomy of an ultrasound

is the piezoelectric block, it's a crystal when you apply power to it will send s send out these alternating waves of sound. these can come in all kinds of shapes and sizes and frequencies, and one of the things that's going on in the field is how we're evolving from

these fairly large machines that were certainly portable down to these hand held devices that were nothing more than tablets or in this case, the size of a cell phone. in fact there are applications on the iphone to have an ultrasound transducer right into

the power cord of the iphone. one of the most important uses of ultrasound is guiding biopsies because it's a realtime technique, can you identify the lesion and put a needle it in it to see what it's made out of. it's helpful for guiding and we've been using microbubble

contrast in a research setting to see how it helps but traditionally, it's something that doesn't require intravenous so in the last few minutes i want to get down to the department of radiology, that's the radio nucleide section, and here we're talking not so much

about amad me but about function, molecular imaging. so, single photon emegs tomography is a mouthful but you have to that a radioactive nucleus can emit a variety of things. it can emit an alpha ray chrks is a helium nucleus, it can emit

a beta ray which is essentially an electron. or it can emit a gamma photon, no mass, but what we call an x-ray or gamma ray, so if have you a substance that emits a gamma ray, that's a single photon emission. and you can combine it with the

ct that we described earlier to get a spec ct device. advantages of spect is that it's relatively inexpensive technique and there's broad experience with it, the disadvantage is that it involves radiation and pon of an imaging agent. it's subject to you this clear

regulatory regulations and it's a relatively slow low resolution method. so we won't spend all that much time with it. very important to how it works, is if you look at a radio--if you imagine a radioactive nucleus emitting a gamma ray,

it's a random event, in terms of emit in any direction it feels like emitting and if you're trying to get an image out of that, you need to tame that gamma ray, by putting in front of it, this led colonnator, that only--colimpedimentsator, we talk about this in the ct, we

talk about the ct anode cathode ray tube, it was spreading them all over the place, so you want them where you want them so you put a collimator here in front of the detector so that only the parallel gamma rays are absorbed. bt that makes it inefficient so

this is a picture of just such a collimator, and you can see the small holes and it's fairly spit so unless you're dead on here you're you're not going to get through the that collimator. and this is depicted here so this will get through but these gamma rays will be deflected by

the collimator, there's a problem here. and the problem is, that the patient is absorbing all this radiation, right? it's the camera ha we're kind of protecting here and it's efficient, only less than one% of the counts that are generated

actually make it to the camera so that's a disadvantage. it's still very actively used but it's sort of passe in the sense that we understand it's an inefficient system. so it requires the radioactive isotope in a contrast, so in this case we use tech netium 99

m and we attach it to methyl disciplinary foster nursed phonate that binds to bone and now we have a bone scan which is a time honored technique for say now you don't have all day to do this scan, there's radioactive decay with a half life of six hours so by 24 hours, you're

down here with the amount of activity. so you reamly need to scan in the first few hours after you've injected. so there are a variety of agents that will work here, mvp as a bone scan, it's good for looking asterisks the thyroid and

salivary gland. thallium can be used for for the parathyroid and heart, indium, for white blood cell count and iodine for a tiaras roadway, here aian thyroid with iodine 131 and then treated, can you see that the treatment results in the loss of the signal and

the patient recurs and he's retreated and the i131 actually treats the tumor at the same time with radiation that's possible, so these days the spect camera and as these two jaws sort of turn around the patients, is supplement wide a convention amillio ct scan so so

you get what's known as a ct scan where you can see the activity, in the lymphnode, super, so, of course, and radiation are our main concern, so we have to protect our workers, the operators so we have led lined syringe holders and we have to protect the

but that leads me to the next kind of more ada vanceed nes clear imaging called positron emission tomography. so remember when we said that for a single photon emitter, the in a random direction with a positron--with a positron emitter, it will give off the

p which is nothing more than a ozatively charged electron and when it meets a negatively charged electron, in other words the normal kind of electron. what happens is something known as anarrowalation and this is matter, antimatter and it may be

science fiction but it's real. the positron will anighalate the electron is the result of that will be two gamma i rase model. setting off in different directions, at the exact same energy. 511, the electron holds, kev in opposite directions.

well, how useful is that? very useful because if you set up a detector array, and you hear a ping at one side and the a ping at the opposite side at the same time nearly simultaneous then you know the event has taken place somewhere along that line.

first of all for every annihilation, you get two gamma rays. so that's much better, well that's twice as good as the spectrometer that produces only gamma ray. you get two but you get directionality how the of it

because you know if you're hearing it here, and there's one over there, that the events happen somewhere along this line of response. so pet scans are highly sensitive, provide metabolic information, much better spacial resolution than specs because of

this--spects because of this feature. you don't need to collimate them because they occur and you get efficiency with regard to how much radiation and how much imaging you need so can you lower the dose, can you combine it with ct, it is an expensive

toy, it's subject to all the regulatory issues and the agents we generally deal with have a short half life, so we--we need to move relatively quickly. so this is just a depiction of what i just said, so the fluorine 18 emits a posit ron and it wanders off and it

encounters an electron where it falls in love and anialates a quick romance and two gamma race are emitted and then we can detect them in opposite parts of the gauntry. so there are actually many things can you do with a pet scan but we inject this f-18

deoxyglucose, now in the 1920s a man named otto warburg a biochemist discovered that cancers upregulate aerobic glycolysis, so ordinar illegalsy as we sit here with lots of oxygen around us, when we get a glue cosmolecule, it goes to pilot project rue eight and it

guess to the krebs psyche and he will we generate lots of atp, cancers take a different approach. now matter how much oxygen there is they convert pyruvate to lactic acidoseisate. it's called aerobic glycolysis, ordinarily it only occurs when

there's no oxygen. but tumors switch it on so there's mirror image colsis, so as a result, because it's inefficient kind of system, you need lots of glucose to run a the cancer gets other things out of it, we don't need to talk about that but warberg was the

first to describe this phenomenon and lou sokoloff, who was a scientist here at the nih, who recently bassed away recognized that the form of deoxyglucose could get into the cell the same way glucose does but would not be metabolized in the same way.

either entering the tca cycle or converted into, you know pyruvate but rather under the hexokinase, was converted to fdg, six p, glucose six phosphate but the deoxythe lack of oxygenot glucose prevent today from going further so it accumulated in cells that were

bring nothing a lot of glucose. like, cancer cells. so, suddenly, you had a very huge way of figuring out what was a metabolically active tissue from one that was just normally active, using fdg. now it took quite a lot of time to figure out how to practically

label this with the petimpediments but it was important to do. so, we can use it in common imaging, for instance this is a patient--this is his impledder with a full catheter in it, but this is a very small lesion that could only be detected with the

fdg pet scan. it's a small polarized kiewl with a f-18 on it that comes in through the glute-one transpormter and is converted to phosphoralated version but goes no further down the metabolic chain. so it's stuck inside the cell.

so we have the positron emission tomography device that produces an image like this, very kind of compared to ct and mri not highly spacially nice, but we can cope bine it with a ct and get this fusion image or we can get the anatomy from the ct and the function from the pet.

so we do this a lot. this is an example of a patient with breast cancer, and you can see the activity in the anter yore media stein umkc and activity in the spine and so forth. now there are lots of different pet agents that can be used, fdg

is the most common, but we can use sodium fluoride, fluorothyme educationalline, fluoromiso, fluorobetta ben, for labeling antibodies and cells, so it's a very powerful technique. it has high sensitivity. very high sensitivity among all the devices i talked about, it's

the most sensitive, and--but, it still requires some degree of so, i want to summarize what i've said to you. ts is the ordener which i present the radiology department to you. it's a virtual tour of the radiology department.

in terms of resolution, the top of the heap is ct, followed by mri, then ultrasound, then pet and spect. that's the least ability to resolve two structures. in terms of sensitivity however, pet clearly powers over all the other techniques, followed by

spect, ultrasound, mri and ct is the least sensitive in terms of molar concentration which can you detect. so we have to put in grams of eye o dine into a patient to see it on a ct scanner whereas i'm putting on the order of nano molar concentration of sdg into

a patient to see that, so the sensitivity is many, many orders of magnitude and then cost, well, ultrasound is clearly the cheapest, ct, spect and mri and pet is the most expensive so you can see how different healthcare systems might have portioned how much scanning is done with

various devices if you are a country that's very wealthy, you know pet is something that you can put on the table. if you're a country that's very poor, ultrasound is a device that's used very frequently. nothing wrong with that but we know that there's some

limitations to what ultrasound can do. so hopefully with time, as time goes omore people will have access to all these kinds of devices. so justa as a generalization and to wrap it up. ct is our work horse in

oncology. mri is used for specialty cancers like the brain, liver and prostate. ultrasound is a very important technique for problem solving, specific things like is it a cyst, is it solid. looking for bone metastasis, the

spec scan is still premier and for any--any agent that we want to get information about the metabolic nature of the cancer, the pet scanner is the way to go. and if have you any--think of anything, any questions, feel free to get in touch, that's our

web site and thank you for your attention. [ applause ] any questions? >> yes the question was does the gada lynnium based mr agent have the same problem with allergic reactions with the automate the corn traof the has it.

keep in mind that's really in the ionate, in contrast media that's going way down. and it's the same level now, between gada lynnium and [indiscernible] there's so increased risk of allergic reaction, there was a question back there?

>> yeah, [indiscernible]. >> so the question is why couldn't you implement it in a--in the same kind of architecture as the other? >> okay, great question. good question. first problem, ultrasound doesn't go through air.

it reflects right off the air, so like if you try to scan a lung, can't see it. sound comes right back, so if you put a gauntry with an ultrasound transducer over the patient, you wouldn't see anything, but let's say you could bring it down, to the

patient sort of slide it around, and you could do that, and only goes,--the more it'll show it, but the problem with that is the lower the resolution whereas if you go into frequency, you won't transmit but you'll get exquisite images of the stuff closer.

so, people would actually design scanners based on ultrasound in the same sort of architecture book for specialty purposes like breast ultrasound with the transition would go around the breast, it really hasn't caught on that much, it's expensive, and you know one of the beauties

of ultrasound is you can take the probe, put it where you need tsee what you need to see and be done. so, the simplicity of it is it's virtue. and of course now, can you put it in your pocket and do that anywhere in the hospital, so.

anything else? yeah? >> so really good question is functional mri scans mainly used in the brain and could that supplement or even replace pet scans. so how fmri works is it depends on very subtle

differences in ox generateddation of hemoglobin, between the activated state and the unactivated state. so it turns out if you're asked to do this, there's a certain part of your brain that gets activated and there's increased blood flow and it delivers more

ox generated eighted blood than was there before and if you scan eugh at a certain way, can you detect like one or two, one-two% change what is the reflection is, changing blood, what the pet is say suggest there's a change in blueicose metabolism for instance if you're looking at

dopamine and saying yes, there's more dopamine here, so there's really two things, the beauty of the mri, and the paradigms are [indiscernible], people alive. and they are in your brain, when you tell the truth--and unexplained people are using it in all kinds of ways it's very

applicable psycheicology departments have them now just to do experiments. whereas pet is so much more complicated. so it's not really apples and apples. it's--they're different that, they tell you different things

but certainly the fmri, whose extremely--has been extremely do i have time for one quick story. one quick about all kinds of ria dimes but one of them was what goes through people's mind when is they're thinking about taking a golf

shot, playing golf. so they took amateurs and professionals and they showed them a picture of a scene and they--please imagine yourself hitting the golf ball to the green. and so the amateurs there's no pattern.

it was all over the place, very lit lit up and with the professionals, nothing. they didn't even think about it, there was no added effort. so just, you know? --that's not to say that professional golfers are empty headed, they're very talented.

. >> absolutely i'm a big enthusiast, we do mri and we do multiparametric mris and some of those things we mentioned, diffusion weighting, t-1, t-two, mt, transfer these are all things that they're not subject

to, fda approval. you don't need approval to use them and they provide, you know added information over say ct scan. and they're in a functional class of mri, it's confusing because the term fmri applies to brains.

that's the term of art. but in fact, the techniques you're doing are also functional in the sense they're purely not anatomic so let's take diffusion because i don't know if everybody understands what we're talking about here. but diffusion weighting, but

water moves inside the water, everywhere, you inside the body you can amove water you can apply a gradient and see how fast it moves and it turns out in tumors the water and rereporting stricted tmove that much because the water moves, so it move into the membrane,

bounces off, it's like--pipe. whereas in normal tissues they're more relaxed so the water is there and can you measure that difference as a diffusion co efficiency. and that tells you how it turns out in the case of say prostate cancer, the lower the diffusion

constant, the higher the grade of the cancer. the worse the cancer, it's amazing, it's totally nonevasive but it gives smu indication of that. anyway, our time--we have to close but i thank you very much. kd--sally --