Rectal Cancer Home Remedies: July 2017

i have survived stage ii colon cancer. i suspectthat you would like to know something about some of the consequences afterwards. withoutbeing too graphic, i will say that basically that has not changed my life. i am recovered,my life is back to normal, everything is basically almost back to normal. one of the things thati was really concerned about, did not understand, could not find any real information on itwhat happens after they take 18 inches cut your colon out and i can tell you that whatinitially happens is, forgive me, your bowel movement is really different. if you haveever had again, just say it delicately if you ever had the g. i.s you know what i amtalking about and this is kind of a norm for a couple of months afterwards but it is nota lasting thing, it does begin to improve

and now two years later, i can honestly tellyou that again i am basically back to virtually normal, i am not careful about what i eat,don't have to watch my diet or anything like that. although, i'm not foolish about it eitherand so i don't eat kind of things that would be bad for me, greasy food that kind of thingbut i have a regular amount of hamburgers and steak and i eat a lot of vegetables andthings like that too. for an interactive tool to learn more aboutyour colon cancer and your personalized treatment options, go to mycoloncancercoach.org.

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pauline mall colin copyrighted programcreated we all brown the auto company annoyed by the national guard and allyuma county haircut broadcast one hundred green managingpartner of board magnate and ralph part prospectingmissing from iraq and nearby our mentor the died night crime occurred near upon at lambeau why don't you speak palmdesert bloom law and portable publicly display macaw

sorted out from the u consistentlyproduced greater miami speed and power to bargain for on the telephone from the public healthof the market el nino zonal com birthdate we have tried a lot of differentgasoline last year we decided we are going tocrack gasoline again is the greatest mother you specified exclusively for allmicrobe regarding a merger to go i tell you throw the river and thecorrect

was probably the most economical guessmaybe we could buy it was also faster and more powerful so did you ever at yahoo dot com fully no-holds-barred account reading reside approximately half thepopulation separate state we find convincing evidence but we'llrun the crack properly more economical for mine and in the congested copy the big citieslike will find a missile from berkeley we find policemen were acquittedpromptly around the clock because of the

fastest more powerful gasoline money canbuy every motorists who will make a testwill discover the reason quietly around the clock pollack more emergency cardfor every crystal than any other brands it is because we opened the crack neverfails to give smoother foster more miles fried not in our great pleasure welcome to calling all cars jereb ph newman opulent county out ofthe loan

supplement fitting that you know i'm honored that night the in the countysheriff's office trying to distinguish list of all important bodies to exploit have been selected back calling all carsparade eel diamond station character which we patrol in yuma countyis indeed the rugged but not quite a while with we're equipped with the most modern typeof law enforcement equipment

fast cars felt that record byu rohan so on but when we encounter a crimes such asthe one where about what you will hear in a moment then it is the backcountry work anddoesn't get bird what from the kind of work begun go tochurch with the old days were called upon to perform iddm strange however that crime such as this

order ones are encountered by eastern krummelwho will think they are going up in a car drawing of art or an automobile industry over you yesterday happiness in the movie this is no longer so where we haveautomobiles to and there is a telephone and telegraph speaking a message

arthur crime faster than they can travel they're playing a separate game yes to the old boys be it no matter how rugged become free are our remote the spot the criminalleaving a trail and it all it's wonderful india and the criminal is bound to move cac anywhere in nineteen thirty three

on the cold winters afternoon remandmahal bedroom in the coming out of new york city they are cheap and the winds for members of the region of the parentsmine baldwin curve believers in the queen that only stopsworking what today's to colin plus you probablydon't of course girls in from the us that we can come up with a bit of anabundance time on the ice cream headband parliamentbill dot april the first game of double solitaire wildblue dot was lightingspent the morning paper in the feeling

up to might suddenly divides problem item tuckedaway in the financial section it's not only that but you with a jerk hale guys get orders vision of papers uh... read thatparticular not murder i guess there is less nervous consolidated quartz corporation ofamerica and not yesterday the purchase of a good hope goldmine from jack eightmd hard rock minor who first prospect ofthe property fifteen years ago

the good hope is located in yuma countyarizona nearby house whatever amount that i'll keep your mind i'm again wheni met your mark this is more important and that card game i know this guy agency remember when i was out in arizonacouple years ago when i worked for reprieve what other justice hayden told me that the mind wasproducing and that they give them a

living and just as soon as he hit the real paidthirty was going to sell out in quick where we think that they had that meansthe holdout so a lot and interpreting your bird with a lot ofscrewy repairs and that's growing at idea he has isthat he don't trust bank don't trust back i don't trust now but i let my money pallet you if you ever need carol banks

images we started mine again tomorrow ifyou need to go uation auto repair a bank i don't understand huge etc if they haveno problem with the anchorage daily i read the paper time know what do youfind a faction charged or the other people's money can react with helpapplicants nobody great tell haven't about are at it leo mein gott say one thing candid we've been living in a cabinadhering to bed at night don't know yet we keep your money give harwell

cape cod allot not even an old friendlike you know when it comes to mind and all right here with your own way where we have already decided that itwould be in a bank yet privation durenberger commissioner heart attack them it doesn't sound like aline killed inthe bellagio elbowed out here who have bought back by one everett

here paid thank god at all eg you've got a bit were and i i think it's done about that a cabinet hulk hogan you remember

okay remember back up here we have ageneral we really don't care what you have made a couple of friends of mineengineers from consolidated court this is misbehavior in the stock marketdoughty and this is an accomplished administerand noticed it daddy and then here i want to look over the good old minefirms in amount to make a few preliminary essays before they startproduction i'm black evidently undocumented people out this way my name's dot not much of a place forthat you've at places like that if you don't mind actually had to writeabout developing

irregular about its own yet uh... and that'll be abig i don't care i mean bloody on just as long as it takes to make ourinvestigation and such you know can't know what they do notknow many more controlled by majumder doctor hadn't sold out western head of the timestamp yet intern at around four out it all a couple of working on my myselfu

reprise what mister in manipur he caught a sort of look at it god to guide the pressler i supposeyou've invested your money by now got over those silly i did yours aboutbanks and things you used to talk about watch dot it's uh... yam atlantis emma thompson and agenda subject or anything but quarters one sleep around

the hotel or anything near volcanic itwould work the report added in bacteria nowthirty-mile bacterial everybody is in the rest of the great outdoors as thatis in best part of the world i'd still want what we pump advocate that might be a little crap basketballput up here with us for a lack of water pritchard any trouble the courseware here have restored foodstamps litigation probably glad we got me to look at and won't have to fight with hard allday c_n_n_ me all right with leaky if

you're sure it won't be too much troubleit would be a great help not no problem software but that's the case what do yousay we are not the convoys we can get a good night's sleep tonight and plan onstarting with a minor role in the more certain takers long to get what we want no word i don't think are terrible be harderthough part at all well pleased because of their first stepfreeman's and your department problem i'm didn't want to do you make

eagerly anyone everywhere dealprospector said in hopes of locating his money back although it was willing to talk abouthis success he is careful not to make a dimension of what he's done with themoney must be written with these travelthey're making preparations for batman begins nearest neighbor tom did wasreturning from bal city and seeing the light of the cabins stopsindustrial a gold com they don't or not this late at night

well uh... we've gotten into city areasof the lake uh... uh... dog he worked with decade combining them delegate towork for me and a couple of mine i think it hotmail minority negatives anyone that the other rooms atnoon or who they were there were no come onancient market nickel murrell don't leave the wrote a piece admitted that we can make deny ballparkneed to get his that kind of feel about a lot of new york uh... will run in amoment to do anywhere

from entering provoke mind nearly everyinch of it but said right i was thinking that maybe if somebodywent along with them all of which freedman is up corporations to get out of the portlandget back to new york maybe you could go with us in themorning removers who would go to the company or ordered they're great appalling mornington his promise tovishal dot but didn't happen couldn't bring them up starts for the mine a few miles distant

douglas macarthur through the mind asfast as possible the top of your sample of warbling all one big bag returns tohaiti one-third of the snakes excusablecomplete normal oversleep saying he will return in the morning once he has left on this calls intocronies aside explains his sudden hurry i'm not sure but i think that'll comethrough this is fact something i didn't like the way he looked at mefollow-up so we've got a point that they wouldn't get out a you find out and thencome to visit with known he says it hasn't got any bill that iknow different

anything that's bad news is we don'tknow where did and i don't think they did level two dollars what we do right after he implied it turned into alittle snooping but in the house maybe we can find it we don't can we stick around until we doit but that might go by and by not being a process to date all week

unpublished frantic pavement are beginning to wonder whythey don't lean unpublished realize that the only way to find the money to getthe two of the way to place well not for the research but how to do this then one night just a thought was aboutto give up all onto the stopped in to say that he's going to balance out aiden gives the catalyst bindsgovernment that the people in the morning that something else

of the following morning that was tossedoff of the city but that is about the possibilityhousing options in their possession of a place the cards on the front door islocked on closer investigation he finds the bigdogs locked inside the house of uk disturbance it suspicions aroused he returned threecar drive to pops reports the constable jill cavanaugh the balcony shows up and usually that is never locked thedoor you know she said you get along a little road militarylogger there

that it'll they couldn't find an alternative doleand you all of the original ahead but he's never lived through about thesethree men you mentioned you know anything about them nothing more thanthat georgia it didn't but they are there didn't seem like minded and is inthe present them out of all about the mind of course you know what you do departments and conditioning at thatthey're tonight dr appt this won't be

mindful of the amount of the couple aman and come up and on and on mine right now i know gooden who heads up is that wewere there i don't like yahoo com if you need meand i'll come up me and i will not want to preferable but produced the career under the right here we are committed torenewed debate about might opponent possible cavanaughoffice of madonna on the board to ponder this informed himthat there's still no sign of animal

behavior house coming to go back to his place comealong to the white house cc holder in yuma notified them of the developments mckillop replied that evidence documentsinvolved cali on their way to balls narrative yet does not come under the president'stenement blocks and read to the clinton and that that now antiepileptic

not giving giving a boost i will gobroke in the middle warlord that we go with that would be better oregon stuck american one cumulative yeah after okay or or or again magnificent little who'sgoing to the moon killed when the world to do to me thatwe are all in a minute

on anything about it over her body work there or what's up well here and uh... uh... falls a little toodifferent i don't think college did you come out the problem inside at going totake a look myself when livingston come under the carpetfind payoff strewn all over the phone throughfour-letter santa claus pieces of

clothing but the lining the bell you can give us a complex overheatingpersonal things fine but didn't stop down is forty four six router it overcourtney cannot be found gathering is not about in the picture ofwinston analyzes the situation oil needed to say that we're up againstsomething pretty serious there's nothing much we can do and itwould produce the bodies of pavement hot or

better yet the fella bennett u_n_ cavanaugh might take a look aroundthe grounds of the which you can pick up i want to get a few more things writtenout here with dubious you'll find anything let me know actoron character outlook as you can help me a lot first of all where the dayton usually leave the milkyou speak of when he left their friend that the jerky reagan at the front porch camara barrett career

you know you know what we really weren'there and that would make me big business upbody of the brokerage and looks lovely and you're listening to right i'm afraid that planned there on the air well it here on this mail now political opinions of punitive maybeenvelope with the has agreed to pay per no anup who would have said thunder

home tomorrow maybe well-planned hayden at a training now minority reviewers hey maybe even aren't sure about what he was goingto do and when he was going to do anyway steady his right now i guess that'sgoing to look level so it's both men missing in the footnote pretty conclusive evidence parity goingthrough but if you have to go back to

well sometimes and telegrams maingrandma get caught in the protagonist mci visit is relevant working against time realizing everysecond count wouldn't believe how detect firecracker spotty travel on to returnback about there's been a little about the computerproblem repeatedly this donnie dr won't be able to make hisreport leaving the written commitment on the david george clarke wife returnedbut he can help to carry on the third the next day at the print shack a two-man stardom and inspection of theground

andrew dirty but i'm going to get rid ofa couple of but did it district needed very observant inhibited rather barnaby jones and avidan arrow react very and our plan private property of or about that propargument wait a minute have look over their fair share saicon manufacturing character greatcorroborative karen starting it architectural record of the program and a few minutes later much trouble welive by park right

if something in the softer a little more digging in the body ofjack eight md but missing prospector lives before the two men a top guns intothe back of egypt looking around for quite find it hard topredict unmistakably the final resting place butdidn't partner drop-off the published in the cpi has beenestablished but the murderers are still missing the park right into this rush to ballstonexciting to tell possible cavanaugh the discovery

who in turn by a showed up on her newbook about of men become old ones to all the more pop and carry on theinvestigation within twelve hours into shopping tools in common with deputies at leastinvolvement doctoring mcdonough position arrive involved pickup heaven on proceeded through themurder an autopsy the by disposable eight-manhop died of gunshot wound eighteen by a box in the back to the endare quick to round on the right shoulder blade and one of my mouth

next a livingston reports to the showedup in yuma wearing what the percent bond issuer i've got amighty good idea of those prevail over the pentagon this building hidden thefirst chance they get well obviously i question the wisdom ofthe violence that was mentioned was that that might buy a gun dot on the be onthe lookout for anything and during the description of making one you'd better get on the right away and moving to get some answers in thedescription eleven out of the getaway

car the things they couldn't have done toget very far before the description without try to get all the straightenedout carl wilhelm now than orbitz the gardens they were not on that's when i'mafraid of for the fifth individuals picture let me know what the you're intrigued gog book that is not all that

uh... it or a brake on bob dole and wasn't hit particular it great ended up putting outon another network will probably be a great it though there were about whatthey did not want on top slalom thanks a million dollars l'oreal helpful but but p lightning likes to be part of thecontract one point received where the freemen ranch in thedescription of that the buffeting stalin

transferred to a stage bound for newyork city on the strength of this new new yorkpolice are notified requested to be on the lookout for the killers and threedays later telegraph message fighters three thousand miles across the publicfish out of poverty lalibela have till three suspects in custody admit the names w mcconnell third suspect whereabouts unknown canyou find the best douglas's wife here if so please notify us keeper police new york city

people each new york city located in the middle of the brother that last known address mister douglas'fifty-eight east one twenty fifth street appreciate your cooperation saying sure-footed human erazo and in response to the detective morningof the new york effective or in common with driver to stop all partof the global market street suite two

hundred and twenty-fifth street yarn ordon't want to take a chance for the florida keys premier reports restocking return of the robert precht located here or i coke record or appropriate predicted are not worth it it is one of the problem of opportunitywith a little bit dull where they don't

have any market when it arrives crapintelligible well autobiography character parekh and career record ripped there are about so you're talking about a dollar forevery where government is not about anyway i haven't gotten knocking on myname is not dot right now i know you're meant javascript they want their permit

all right right that uh... that this reporter for theprobe once logged in the billy dale the mandenied any knowledge of the crime in idea lou dobbs denied everything but he has quickly identify when confronted with the proof's admitshe has done this but claims he's innocent of any crime notified of his arrest carol connorobtained expedition paper but he doesn't want to new york

but the freemen and you've got to bereturned to the yuma county jail they're placed in separate cells are notallowed to communicate with one another attitude while they are locked in theirindividual cells that make the biggest mistake mistake to bring the prosecutorsharpeners office noobs within the u i thought you'd want to this butcherwrote for one of those people of mixed up inthat hadn't therapists from good words

three cities is savills you must labor productivity crazy on theday of the murder there would be willing to pay them foryou site mu very interested would be a bit surprised at this littlepiece of paper wouldn't hate them ever wrote on the morning of operating bikingparticularly in the republic philadelphia and down o'connell facedthe angry mob in the problem according

to stand trial on murder charge as a result of incriminating no hidden uplifting pleaded guilty of the thingshe acted in self defense however the jurors or not swayed withthis resort and on the fifth day of october less than a month after thetrial has begun blue douglas you have been found guilty offirst-degree murder that you anything to say before i sendyou with self proclaimed through douglas after hearing the evidence offered inthis case

is the belief of discord if you areguilty of deliberately murdering two men report is my duty to certain to be executed inthe legal chamber but the state prison in florence make god have mercy or so ago you movedup but then again you know i i i i have heard with adobe internal condom you have been found guilty of murder inthe second degree do you wish to make any statement beforethe close

that's the sentence on you very well because of certain evidence submitted itshows that your column with at least beauty of this crime i sent them to do five years in theflorence penitentiary and maybe this is the key to thefutility of trying to break the law willett w i'm going to be more severe with you you're a menace to society and as awinston i can give you

however it is a sentence of this court that youshould spend the next twenty five years of your life in confinement at florence penitentiary alittle not leads all the states in per-capita consumption of rio grandea cracked up to me evers-williams i've learned that realbranded patented cracking process produces a gasoline but give greaterpowers even mildly another brand something to think right

and inviting their engines of high-speedover long distances and desert heat as only until they learned that there isone motorola which never breaks down didn't play a motorola and you can get it in tamper proof can wherever real ground o'clock kathleen asoap because all black the petroleum jelly isexpected from simpler more toilets they never got him or what we have high speedof the stringy your car won't do so much a little whenthe runs on sinclair because the part of the current carbon

so easily are already removed you've got a really pure oiled neverfails to get adequate lubrication this month we especially want everyone to go itwill be a brandy station and ask for a copy of the new double-sided calling all continents you'll enjoy reading the true detectivemysteries the police movie in radio news and everybody would really want to readabout rio grande is junior police department

under fifteen valuable previa ask for your pre cops wherever real ground-based backed out onthe missile bowling on cards and or you're going tohave to guard against later broadcast one hundred degree disrespect litigationunderstandable the q this is your medicare president clinton having a good night calling all cars are copyrighted programcreated by the real crime the oil

company assumedly falling on hard times in ourcar broadcast one hundred thirty-four woman overall grade a dead body in thefrom mental with uh... every three to the fire into the livingabroad at macquarie org randy quite definitely sometime today and pedestrians and motorists out of theway about a police car or high for firing pin ornaments on a motorcycle every second compliment silent spring

so that that is in tel aviv that operatethese emergency motors practice gasoline that they can climb the most convincing proof of theall-around superiority of rio grande effect gasoline is the indisputable factthat wherever it so it is specified for more emergency cardthen any other black how do you choose your gasoline you've got by any gasoline of the mostconvenient station or have you discover the but drivinginto the independent rio grande estates near you

rio grande deepak naturally the thing that really matters specifiedfor the plan the fact that the most powerful emergency engine at no extrapaul then when the parents bring and by thepolice car or fat filled with the knowledge that wheneveran emergency rises you'll find a police car performance from your own car out of our pleasure to present keithjames e davis of the los angeles police evening friends the case you're about to hear dramatized

differs from the average police case in that we had no inkling of a missingperson or the fact that a crime had beencommitted until the murder confessed it may strike you that as a result there was no work for the police to do but the story you're about to hear will convey to you how much work therealways is for your police to do before they could call even avoluntarily confess crime closed regardless of the emphasis with which aconscience pick a murderer may compress

there is always a chance for somethingto go wrong before the case goes to court or while it is being tried it is the duty of your police beyondactually making the arrest of a criminal so completely to investigate every angleof the case that the prosecution may be providedwith an airtight case which no amount of legal acrobatics by the defense attorneycan break down was the work done by your please in this amazing affair

of the warm and with the heart of stole warm evening in april of nineteen twentyfour high above the thirty sweat beads inautomobile comes to stop the normally promontory on the panama cappella thing occupants of the car mrs margaret willisa companion for clinton webster clicks off the lights the betterto insure that lonely beauty of the ocean he turns to missus wallace beautiful isn't it margaret

terrible better i don't think you can look at it it was the matter with you devastatedbut but why don't want to play here i can treat you are we showing me a picture of an ocean orsomething and saying isn't it beautiful now and i ask you the same thing aboutthe real good economic and stand a look at it and i can't figure it out willhave to begin eating out there detectable ob of and we're going i

the matter margaret right then something is majors areedmund no you haven't done anything debate and talk i'm not in the move went well but work wherewithal in bedford is opposed home of course you're going to look at anything youdon't feel in the mood to talk but after that it does i'd like to have a san fernandocharacters and prepared

they would go out in the u i'm not out for a tour of the countrytonight i'm tired i note that my mind i want to drive out there definitelywhen i don't know whether you're crazy or what but i'm not going to do any suchthing ricardo then i need to read right that i'd get that had taping tell mewhat but that there will be a driving it it's about doctor baldwin wrote about it demand that totally like within youwanna here or whatever

you've been that child that there depressurized havoc job even that come to have the time to beccadot com usually want to do with it that what you can only security that ihave a good chance of doing it over and i seem to be gave himself up na beforeit's too late everything i'd headed to thank you deplete the party barbell became becauseit had not

got off my head and shopping half of them and doing line understand we'll have the best you won't handyman no i won't but i'mjust get becomes instead much comedy only a little ladies we canstop on the normal great i think and henry do you have entered the start ofthe great read ahead of his resume is actually a good place i'll stop butnothing templeton pulled spm that chance we could be a bit

i had to go back and the question nowhat do you think that is part of the event is in a car lights behind now no i don'tthink that and that is that nobody had secretary mankind optonline think so you're betting now help me that the drug off the rack nadia matar urine

advantage get it up on top of this program a little frederick manner that hello hadi recover the certainty of its clear belowredorbit contains intrigue had nothing to topic and here it goes now let's get outta here he can be seen to negotiate like i don'tknow only lets go im go down and look

i can't leave until i know it completelykick butt naked you would have been thinking about and to hear it did not get back up bulan forthcoming com you're making a mistakethey got that mister edsall probably i'll be right back particular way and back to korea genomic dharmesh

i'm going to make up up i didn't like it haven't bought the following morning inthe opposite effect chemical even to look a little bit while her uh... for it resided and fred ladd lieutenant nothing morethan a day might be you mean the woman but you started bywilmington saying whatever issues you

principle in iraq reserves and sixo'clock this morning he's got this area alleged that that you know we're all going to doa little bit and don't forget that you didn't like the caller would be at which is a real calamity lieutenant even at made i think we can just see you i killed a man

you walk at tiananmen that's where the state woodridge il be limited defendant boarding unit dumping tied to attack me you mindtelling me your name wealthy margaret whiting no where and when did you kill is thatfriday morning my apartment campbell eight weightseventy ever got the bulls but you know

i can do you get to it respectively d rooted in europe louis unique that will try to keep cool and geography future reference uh... organizing the party of seven menincluding inflicted five-month don edwards told the detective division

lieutenant stevens lead the way to apolice car and start long drive up the new all grades there's little conversation is the firstcar wars along the highway leave the city limits dot smile at the mile behind it but more than two hours after leavinglos angles confessed killer suddenly points to aspot of the site of the role they have been betrayed by barbarabarbara dot net bottomless

down there my wallet domino your resume as well that all right helpful of all of that bottler sect of complications act miss as well as you positively identified the body doctor benjamin baldwin

who's trying to those lines had to get the body of the air i thought about the column i don't think it would ride you know i cannot get offline yourbecause it was idea now i popped dr baldwin model linda told me you brought ducked thebullet out there in his own co in my com unforgiven longer i think if they can stick in mypocketbook he tenido tremendously well

of picked that up to them of went to the political spent the afternoon and when you say you killed this man friday morning came to be the consignee if they comecloser to the conflict armful yet at the info assigned to the money back pocketabstracted is the money still in his pocket was with us

i don't know what it is not i get to phnom penh listens well we've been drove north korea value money both of us it'll be really good of you know if youlie about it it means that went death that the otherand yet uh... but the bottom of the room known idea

miss lewis uh... your wishes from all white i'm not well and that's what the hell throughputbolan bought him a strong certainly nothing new nothing about that put dynamite here's a pretty heavy man who loves andi'm a very strong women yet for the body of the phone call by mycount mister you're right and flat

you don't do that and the monsters land admitted madam more than the left yes i have not been here before question of what you're seeing and howdid you get up and go into the back of your call back that have wanted to look at all of thathe didn't economic data don't talk to files thatare going to move when you walk i think

he didn't know anything about it and howto explain the fact that helped jews or the struggle to slip by talking about it but out here i made it helped me run with that line yet that last night items did nothear he didn't know anything about the content of the trunk until you reachthat spot no he ran thinking we've got to get back totown and buying this book but uh... fiefdom you ought to have a lot of interestingthings to tell

thrown into a thing to look within thepeople who put them on to them for design two detectives the unpleasanttask of notifying the so-called of her husband there and instruct another to bring in websterthe question retired unthinkable inflicting ministering in the first woman leaving a lot of things aredifferent views opposes webster fellows in on the deal that looks like it somehow

ideal who's driving brotha helping to get rid of the trunk of allthat and not having something to do with thetime just jumped up and john mighty and just left him a lot ofquestions thing i can't understand is why missuswill is going to all the trouble of getting rid of the body stand what he told us about doesn't make sense not so sure about thepoor makes a lot of times with the figurethings out another way

will just supposing she meant to pumpthat doctor often get rid of him when she goes through with it stepped into the trunk at this web that the driver out in thevalley uncomfortable and the prompt inconvenient pleasetilted occupant out on the ground for the world to see and what than the ones you have intimatedifficult but because although she figured out that aconfession will help us solve the front door

still doesn't explain flight if it was so fast give it a little trouble make it looklike it was the emperor's most likely because it wasin the always read man captain edward as they were that websterfor lieutenant them involvement we'll probably in a lot more removablego and i'm kathleen requested factor

spectrum underground dependency retinoic absorbent room it is a short as possible i approve you or your hair looked or aperson ideas that go all right figured you'd be up for me before long want to do and you are a few questions but went to the repaired carefullybefore you went through what do you know about the well not awhole lot

i guess you already know more than i doif you've talked to peg who take part forgot you didn't know that the name icall missus will is fine sort of a pet name any i guess so whendid you vote will not looking for a little drupal last night when last month when i don't know exactly what time itwas but it was when we are driving in from the beach did she tell you about it before you goup the place for you calpers board yasir she told me about itwhen i refused to divert ur san fernando he said that you don't have to protectour honor and asked me to help her

didn't realize that you were in acriminal in the act of committing a crime unit already bankamerica whomeverhad been committed but at the crime problems both of the political turmoilthat world yes uh... effect too realize our interpreter dot or procureweapons yes certainly i didn't have anything to do with the actual killingled them into the sea i'm inclined to believe that certainlyprovide lieutenant honest and but until the time that we can prove it one way oranother i'm afraid to read the book you as amaterial witness you may have got to

stay in jail that's right vital area if you remember anyadditional thing you think we might be interested in but that would uh... you don't knowabout tel aviv non-competitive so further questioning didn't hurt purplepwnguin oh most of all

we realize but those of the purpleexpert for him under those circumstances removed i askyou some questions understand acrylic hamburger put the ball adopt the ball and mentioned sellingthat car he discussed it with me to go to she was going to the local level as well remember anything about the last fewdays that might be of interest to

ever several things it seems strange tome became i didn't realize that there may be thatwould lead to let you know pretty weak what worries who but referred to through the night we had the most improvement subject ofthe talking i suggested that dr cohn to put us in the future is goingto buy candidate yes he did

asked about the fact and i have nothing i'm going to benefit i think we need to become by at thoseboth him and the money between the two nd next morning you have to have something to do thekind of the moment of truth friday uh... republican a lot of people wrote doctor's office from time to time

that report is not complete and also when you when we come inbecause the station for getting tired of waiting for him we've gotten them intothe office of the whole no nuclear conflict glove at ucr she said that he had been having amoving into the car mehmet and costume she bought the car shipley chant

after how much a people's and she said i think and seven hundred and fiftydollars change yesterday we third yes but i don't know that she could notbecause i haven't talked to him from twenty nine to talk to you champion anything for and whatgovernment phone outstanding issued by the day before the doctordoesn't home thursday night but but he said he needed to come in thenext day you're going to have it

one of the things you said somethingvery cryptic to me xiang since my husband was a drinkingthen and i said no she she said that it was the government of the different thatmorning you have to fix it it comes to come back into the morningand give her another driving lesson he had and this was in the afternoon already covered by the judge didn't seempossible can you coming back to me

mexico football and i don't need thatmight lead them to lead like seven days but would like to putthe entire time to questioning what breaking down market with the selfcontrol it at the end of this time they are inpossession of these damaging but missus will is playing football frontbut they have the mother falls acquaintances hills where policeon top of the doctors latest ten o'clock on friday morning that he had not beengreat second an employee of the press belongsapartments informs police is on the morning of themurder he delivered the trump computer

that was apartment but when he was about to leave sawmention protruding from a whole closet over what looked like there might beacquitted you hadn't said anything to leave it at the murder in the papers from several neighbors of multiple if itis limited to a woman of great strength of the baptism in the same temperament right butler prepares several weeks ofpreparation bargain willette is placed on trial for her life

report that program and will that work for your call several preliminary witnesses out there and then court probably the capacitywithin your problems waiting for a look at the now-famous woman deputy district attorney market but missus will is you realize that you're under oath whichwas want to tell the truth the whole

truth and nothing but the truth i do aswell not to say that on friday morning apriltwelfth of this year the disease came to your house todeliver a college would purchase the baby four for seven hundred and fiftydollars that if and is now the fact that in reality had not paid this man adollar hunter cocker directions missus will is would you mind telling meexactly what took place in your apartment on the morning in question just tell me in your own words

doctor baden dot the car over about intercom and he was drunk fired multilateralproceeded the automobile morning last week he was drunk and he said then what happens is with us you're going to get into driving lessonsi think the competent approach and suddenly came up behind me and tryto keep cool continue please

when he tried to teach you what did youdo i'd try to get away from threatened at one of the trip any flap a contact the white house to betold in fact often film when i came out of contact robyn pendingtheir inc dot prepping so what did you do then after two p bill he started talking but that's because i think that the gunnovatech what kind of agendas as well as revolver

is gonna marked people's exhibit numbertwo the ones as well as discipline thank you you may continue i don't believe that you can but he different yahoo dot beyond what you holding thegun pointed at him why did you call for help over neighborsall around variety yet you'd rather shoot 'em andthen have a little over it i didn't think about you didn't thinkabout is white with maybe the actor yet

sectional missus will is talents in your own wordsjust what happened from the point where you grabbed you by the alms to theactual shooting double-dipping backing down the king still holding admit can pick up a time to get back into thecomplex pulled the trigger if he died instantly i get to grow out of my apartment

i confirmed marcel characteristic cooper record of it albeit while live mister laws just made a share is accusation you all for evidence to this courtconfirming it again dora darwin i convert your responded to prove that paragraph there with the cattle drbaldwin and of all this trial is over i whipped

but the defense attorney's statementproved to be no more than the last minute desperate attempt to bring theretrial and after reviewing the fact dot crayola submit the case to the jury don't tell her to get out of it cortex is a very ominous monetaryreserves and which remembers her revision europe recruit for realtorcoverage of campaign room recruiters who you're good or prepare inyears remarking serious issue for us

parental just jury reached a verdict it we have the right but plenty of the court rated please rei that you have a uh... depicted abid ewga you're for the reason why this collection uptheir sense of this time

no real romance audit was stand and face the court been found guilty of murder in the firstdegree uh... for the predictive is court that you shouldbe confined to the state penitentiary for the duration of natural light sold margaret willis what's up to the penitentiary for life

there to pay the penalty for crime explains crime this inasmuch as it was definitely prove that self-defense was not the reason for the murders the only other reasons watch the desire to want doctorbaldwin's automobile it seems incredible that anyone impersonation of air force sensors

would resort to murder for some smallagain such was the fact in description like case thank you to dothis photographs of missus will is frontmurder case in the complete story of the amazing crime you've just heard aprinted in the past meeting calling all cars new a better and better publication thismonth than ever before with several true detective mysterieslatest radio one and movie news and descriptions of fourteen get thatreal grand a offers free to everybody

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sacramento police patrol loosely fuel from the new studios out-patient care pre-k in sacramento keep helena good evening xuat obvious to light a local piles of my department is really not my case

into the case of that cops sergeant in charge of the narcoticdetail the sacramento police department this broadcast in fact might be considered a tribute sergeantcops lubimov in twenty years an unexploded result sergeant cox is an internationallyrecognized the body i'm not conic criminology he actually would like strawberries heled the police officer

intrude crusading spirit against thedrug traffic four years ago i thought it would fallapart legally vested in him and he goes further down the line ofduty forty calories on a limb such campaignfor narcotics control all over the united states agitating for adequate legislation campaigning for wider public educationthrough the dangers of narcotics it is a great pleasure for me to be able publicly to come by and sergeant cops

for a splendid work march fourteenth nineteen thirty four in a deadly lips i just returnedsacramental to shadowy figures me uh... chileans reportedly we'll have the amount one twenty or themorning five dollars he's you might want all right let's take a look at whatyou're hearing or a huge your last two

years we've been watching your collisions white about right but she will not be there bad guys here and all that we've got to win the activist sale get picked up your way out about power and the guy

letter dot com orchid if you were put into question usually how you do not think imposing uh... setup he works for us like that then abruptly but i was was it uh... what i want to know villages why did you get that down

with no uh... cum laude that pretty weak where did you get it mexican film above it and we do not know i had to do their mission you're adorable mexicanbrand name when they don't like review for dinneron the mexican federal has endured but the spot where he was like guinea or the mexican trainor

chippy had worked on his hands they can nineteen thirty four startup costs and his partner detectivedefinitely coming working day and night to stem therapidly reflecting both marijuana cigarette into sacramento raid the rooming house power not gone but you don't know all that

with what you got another one in americaprofiles insurance needed it like e which expected i do not know in any event now might not know all mad you got any kick picked up on that when we put you awayfor a nice long sleep up quickly well i'd okay

yours market about where did you get this marijuana michigan vishal what mexicans are alternative on the mainland only making team mexican debt right etc etc a loving quite enoughcaught what it is mexican democrat red twenty times

as here our matter though are coming and hisname mexican game well when you get that government is nota little but if you have to give money one appealin the way that this is good hinted at it that as quality like a lot more evi wonderful days collection but what

ectopic california plant life in your i do not know anymore fremont wasn't question ever suspectedbut in the middle of the field all my messages then what no one can hope will tell whether it is and then the following the raid in allthis all day the plot the governmentexcitedly reports the car an epidemic

vision subject estrada reporting on the late thismorning acting scene spanish while we werebringing them over he said exchanging more granular wilcox teamdispute exicted jim these for you you know that that is unit at the break we've been looking for much of a break

must be several hundred wrenches andyou're working on it that's ok with them all well alternative agronomy marijuanaabout we've got to figure something that youhave an excuse to get out of the latches and how about posing as inspectors fromthe problematical plant nasa we get to see the form of the owners ofthe writers but that isn't enough maybe our mexican game is working onwhether these rafters

growing is marijuana a time when youtake three to report that's possible the force might never get wise it only takes marijuana ninety days tomature the flight away but it's growing that's right izzy we've got to figure out some kind of aget it doesn't get is among the mexican restaurant

you worked on some of the writers aroundhere you got any ideas how to get close tothe exams much haven't something's rotten seven something was a little warranted reading didn'tpress it soon so something what we sell biology and the big story

narcotic officers say interventions that is what what peddling in reverse books magazine and not another three we've got to have a lot of good peoplein person sulzer political refresher course we'll get some samples of some waterblanks and political leaders sounds reasonable to her and again it's close enough to them towatch for wartime actions

after all that they are on the quilt what do they go there makes convened a sad and tragic rose trying to read but they must not be too expensivepeople fail those they have a much much love laura and we've got to keep it upbut i had a good you're going to help me to get out processing and then you're going alongwith a selected and everywhere we may need your site

but today's equipped with hopes ofswatches tape measure the two authors in the mexican assistant beginners systematic and the civilrights is a few local they are two really good papers to you that without theprofession fillings you've got to see you but never managing to meet with themexican with what sundays m then

after they had visited nearly forty right with discouragement as often sent them to give up thirty-oddeclipse all part of an sacrament the big italian who owns the place meets them on the porch of the lamb chopbenidorm audino we represent the western habitatrecovery incorporated

psychiatrist you went to the followingnot too many of you know just take a look at our line of samples legislative actual that popcorn out there what is the sort of work thatyou know how about them and other places when it was your year-end for that itwill take your word for me now villanova selection of above theprograms for him where they don't worry you're forgetting about it the ordered

what do you think he might be interestedin is at the close orchid over there it's awful you are central or after added an absolute gloucester the shipment of pet and there

acting because you weren't even mindedwards mr smith and mister valentino chronicle gardner festivities socio charlotte as a get out the samples valentino i doit here's what's on the stand interceptors uh... expanded there's a very popular number whostarted just what they're wearing a new

york uh... like that a lot of people on here the but stuff and an excellent choice just look at the moment racially e you'd look like a fashion plate msdouble-breasted modeled the defendant yet heard that alleged crossed the main issue like that

where we can pick you up for this modelfor forty dollars floyd nala or you think i got pool for the lives ofothers almost is booked riddle is twenty five vikram dot admitted that what is thevery best for the money vision my travel i'm not the one who pays for it dollarsworth of course but i'd like to outside by the bass unexpected baikonur bought someoperational

i didn't understand it first these published fuji film made item buti don't like the films where ka sometime when he got some good stuffbut i would estimate of the defendant said about the entire ratified samplesup in sacramento but that did he get it and bring themalong that they had about an hour by those that custom-built suits thathundred-dollar like you're representing client yet actually abroad is we we didn't expect to encountervanity or face to face

yeah uh... and many other around here but if you could give valentino anappointment and sure it will be pleased with that wear saree said idea please i rememberon sunday on the media then well uh... brother's restaurant you know that but florida senate i let me get a shot basically a book okay okay

about them and added to that hundred dollar line along with that what's on my hands leveraging forty-fiveadjustment if end where might you get samples of one ofthose sources and some place that isn't all you have writtensomething now what is he was arrested now not yet but you have a problem that you willah... atlantic guided by instructs related to reconcilecollection

which has been sent to the fact that thepolice for mailing so the tip of the at the wholesale may not have discussed sometime jose brings up this person probably contained in his letter i have a problem in my hands stretch of n have michelle did whatisn't have a letter from a dear friend of minesan francisco

watchdog on it or those you let us say here religion instead my good friend and piano do something for me well you everything that's in thesacramento bhavik setting stores to mexicans please keep your eyes and ears open forgoodbye at my watch

mother while second-hand of five hundred biographersthat much of that prepare one nice commission if you can buy a permit period of aprice understand their someone of a fewminutes like remember somewhat inventors my time with their stuff and he identified on their lesson planstuff we demand a happily ever after fishingboats in the cameras and backers and let myself it's just good shape

i feel inclined to invest in fivehundred bombs i think the prices going up youthful make a good day for me my reward you girlfriend and i know my kids keeping up i don't know anything about my laugh i've got too much to myself

i can go to a dot m would definitelylook for my wonderful fun unborn ad-aware disappointing he's a very old friend of mine you willnot go through the sampling team well-being or i got to play kiwi tenthousand pounds of my twilight measures that and they will only tell you fivedollars at bangalore candy fortune to have met you lipid thousand bottom i want to bringthem raise not on the ranch he's one of fifteen miles fromsacramento these money what i've never been on theranch

i gave the start of another player whencan i get defied are part of my friend they will put everything away before ican't believe it you know fully matured yet academic prep another reckoned that themarijuana plant your bumper leaned up my good friend banner you don't know how happy you make me well i guess i can working he's known to all the people around that mexican gene

development they would like to leamington needs ofthe marijuana restored fifty miles from town then he said that it would not people in the court for a week marijuana can be starting to lookforward to it my hunch is that he gave was they wereright around because of marijuana is on that ranch redirected

and remember that italian told it's beena messenger whatever his name is is leaking forty five acres and forward with a few forty then we'vegot to find that the uh... first of all we can come over here and then latermadeline federal we're going down there tonight well unworkable quote from us there's notelling what we may run into hello before midnight leave the car parked a mile from therent and start their investigation of theitalians want

pretty hard going or that they are not utilized manipulative stuff is growing in thisfield looks like with white covered with expereince mood but it does with grandma here wet matter carreira irrigation ditchesalcoholic ultimate thank god with red

who brought along star at market price explicitly written for you work court side tell but i don't wait a minute because i was relieved to see themoonlight also there's no wind blowing customer orderfor you working plant corn readjust to fake it

for governor one of the program with a few days ago particularly here before somebodyseasons like recover from the kingdom of world you could beat this evidence in court say that he didn't know what was goingon a plan after all that one of the wheatubiquitous the girl that we can't let him get awaywith this don't worry we won't tomorrow morning we'll give away anotherjob to do

okay that's going to be because theminute with you collecting a few relieved for souvenirs automatic chemical analysis of the stuff leverage today elective office to your friend mexican m relocated here last night and reports of the samples withoutantibiotics we don't want any setback

certificate dot i want to get back to marijuana from him and having possession and sale instead and interpreted in the san franciscowhat's the fact embarrassed to staff it before it died of a lot of money in fivehundred pounds you fall apart report back to me as soon as you may berented jose interviews mexican gem othersmentioned fieldset he returns to headquarters in reportstwo thousand cox and detective tom

everything internationally when we may correct he called me to be outside hamburgerjoint in big some at one o'clock in the morning he would bring him i wanted to makedixon at fifty miles regiment others and prob that that is what your program headed somewhere betweenthe ranch in dixon so there's no chance of being caughtreactive actual sales

would be released its report on just to make sure callous what scratches stock you voted fiction and wait for it but the chances are a lot mitchell chances are you'll be unfair by oneo'clock in the morning but they have to stand on that nightcarpenter almost all the car off the road and what that link leading to the ranch

and couple of hours make your tunnel mobile okay tell us roll across the road outfit that there were dead quit or along with the car broke down eliminated the what about what of that

colorado garment workers all right what what the word but about records on the street craft or bought suspicion of possession ablack onyx at the moment at about but i think you'll be for act that is a little bit now i'm going to buy a lot

rate with a number on it is overlooking port-au-prince and algata marijuana monotonous pennant intercontinentalsolely are placed in jail and the following morning cox and thomasreturn to the field of view that captured for the first time and date is a professor from the californiacollege of agriculture hello dealing with the president i would not believe it

it's the most scientifically growneliminating overseeing temperature at which the son of a good and the capitalization as apparently hisintention was to match them out one of those rolled up on the outside as yousee a friend of nicole but i wanted to dry and no one with a captain given what would youestimate the size of the field to be cool dot five acres five acres

you know that alistair utilizingprofessor that this constitutes the biggest marijuana seizure in the historyof narcotic enforcement indeed innocent that have been anything like it before that marijuana performance a correctit's a great part of the matter with us burden of applied his talents torecollect our culture what a scientific probably would havebeen and professor there were would be a better players ofa lot of markets were spending that time figuring out a help people instead of onall of them there's no one of the oakland himself aglass leader

but it is impossible to transport undercover carbonite how to cut down and then bone they won't have time to mature and in the meantime cox interview justprisoner in sacramento jail prana forty dark real requirement tough for me you from that anything on theirtransplanting well that the other killers land mines

feud judiciously from that italian i was growing cronin lettuce and stuff how do you explain the marijuana has bothered about it ulead grows well not this locally this was planted irrigated rate and believe me pander to the beautifuljob nor what you mean i'll listen man they've got a half a dozen peddlers wealready put away looked at the vatican

practicum with marijuana said there willbe to blogging apple panda i might use that against japan and uh... that and fog and a marijuanawithout a new york back last night and explain that belong to solve it i think you would think a how would you know at salesman valentino is working for usyou know he'll testify about your willingness totake in order for five hundred volatile

raise you got me all right ratio wrath forty-one imo well just off the record i'd like to know howyou ever come to play such a long ten because i'm a gum like it i'd like to leave group and i like theparadox here president yeah that's part of it i feel if i went on forming on mynightline never paying off

and she was a long shot to plant johnsongetting it all at once because mid twenty s tons of fun to readthat might wanna met with the story that five dollars abomb as profit yeah but you didn't sell it flat out at thetime all you got out of it is a trip to sanquentin which i'm glad to and they lost the responsibility of rick said he'llwhat the responsibility

let's say for instance somebody who smokes a cup of cigarettesmade from your marijuana might have gone out and get the money inouye you would have been beenresponsible for that matter ethically if not legally i don't know good things like that i fear that the amount of course wellenough to some of my long i will get into trouble anyway altman you don'tsmoke it from uh... not the main and this mock

will pay not nearly as mexican jim wasmarked a decidedly superior met but he wasn't smart enough to see thefutility of the gamble that you tried to get away with he lost to the tune of six years in sanquentin and his partner so thay was deporteddirectly sucking cocks received thecongratulations of narcotic enforcement agencies all over the world for the excellent work which resulted inthe seizure and destruction of the

largest field of scientific allegromarijuana ever attempted how would you like to ride in a policecar raag rendered overkill although acrylic a police car before making your ownheart when you lose rio grande e technically saying that the labor power more emergency card then every other brands

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>>> okay, unfortunately the doctor had a conflict and so she's going to give her lecture on september 30th. so i switched with her, and i'm giving the lecture today on small cell lung cancer, the second speaker is jim gulley, talking about prostate cancer.

so all of -- and then in terms of announcements, we now have within telepoint posted at the website, s and then the video cast is now archived, so the first lecture you can call this up on your computer. anytime. and you click past events, and

you click lectures, you scroll down to traco, you'll find lectures fro from ten years of traco, we have over 100 lectures posted. everything that gets posted stays there, and then you'll notice one interesting thing is my address has changed, and my

phone number because my office was moved last week from building 31 to shady grove, so that's good for the 20 people at shade y shady grove, now youcan pick up handouts in my office. that will help you. so we're going to lecture about the small cell lung cancer and

this cancer kills about 25,000 patients in the u.s. annually, this is about 1/6 of lung cancer patients that die, and all the other types of cancer are nonsmall cell lung cancer, small cell lung cancer is a neuro endocrine cancer. chemotherapy and radiation

therapy, the tumors get smaller but relapse occurs and tumors grow and they are often unresponsive to chemotherapy, so the median survival time is less than one year. so the small cell lung cancer, this is a biopsy specimen, you see small cells, what you

really see are nuclei in dark purple, it's very ordered. the these small cells. and then when you look at them under the eelectron microscope you see the granules, like what you see in neurons, and the small cell lung cancer as a result makes and secretes

growth factors. so lung cancer symptoms, well, the first is the cough. and then you have chest pain. your nerves are sensitive to all the inflammation, shortness of breath because part of the lung is being taken over by the tumor and you can no longer

exchange the co2 for oxygen. often times people then get infections, with bacteria, pneumonia, or they will have bronchitis and then worst of all is if you cough up blood. then that's an indication that your cancer is of one of the higher stages.

traditional it's done using chest x-ray, but then one can also do broke they can stick atube down the detroit t throat, needleaspiration, sticking a pin into the tumor to see if you get tumor cells, remove blood fluid and look for cancer cells in the fluid. you can do surgery of the lung.

and what's in vogue right now is spiral ct, a study was done by the division of cancer prevention about 5 years ago, and it showed that if you have spiral ct, and then it's treated, if the patient has tumor cells, then you'll reduce cancer incidence on the order

of 15%. and so 15% of 100,000 people is 15,000 people. so lung cancer, we're always talking about anythin bignumbers. this is a chest x-ray. here you see a tumor on the left. a fairly large tumor.

this is a ct scan where we see there's a tumor here on the left, and with treatment the tumor becomes much smaller. this is the bronchoposcopy and you see a tumor on the left. unfortunately, usually lung cancer is detected when it's in stage 3, stage 4 it's undergone

metastasis, that's bad. we can stage us ewin it usingthe ct scan, mri, pet scan you'll have a lecture about using isotopes later in the class, cancer cells will pick this up more readily. you have radionuclide scanning, bone scanning, tests for the

bone, and here in mediastinoscopy you're looking at lymph nodes for tumor cells. generally if a patient has no therapy survival time is on the order of four to five months, if you do surgery, the patient is in stage 1, increasing survival time a little bit,

radio therapy will also increase survival time a little bit. and these are some of the agents used in chemotherapy. we used to have a lecture, but now we emphasize newer drugs. agents like car bo carboplatin,the cancer cells can't correct the

genetic material once a mutation has occurred. and then other agents are inhibitors, you'll hear a lecture next week on this. this. then we have agents such as doxorubicin and we have antimitotic agents.

vinorelbine is also used and agents that interfere. so you note chemotherapy agents mechanisms.erent mechanic in the '70s clinicians started giving combination chemotherapy. this would inhibit the agent. vvh-16, different mechanisms.

the clinicians abbreviate this vp-16. other combinations, ifosfamide and carboplatin and vp-16. it was popular in the '80s, 90s, and 2000, but the result was for lung cancer very disappointing, it didn't do that much for the patient and

didn't cure the cancer. so you see here an approach to use radio therapy combined with chemotherapy, and this increased survival from 10 to 34 months, five-year survival from 6% to 30%. so a combination then of radio therapy and chemotherapy can be

beneficial in small cell lung cancer but still the patients are going to die. so initially, small cell lung cancer often responds to chemotherapy, but then the patients undergo relapse. the chemotherapy becomes ineffective.

and this is results primarily because of the field effect and with lung cancer it takes so long for it to develop, 20 to 30 years, that initially you have one clone of cells, the first clone grows out, may be responsive to chemotherapy, so that clone is killed but then

the second clone grows out. the second clone of cells is resistant to chemotherapy and that's what killed the patient. so this is what is referred to as the field effect. and then small cell lung cancer stasis, gets toma metastays is,the the brain and the patient dies

in a matter of weeks. so some cancers, the carcinogenic process is well known, such as colon cancer. but for small cell lung cancer, we really don't know anything about how it develops. and where it comes from. in the lung, there's the neuro

endocrine cells, we don't know if it's a precursor or if it's stem cells. so the carcinogenic process of small cell lung cancer is still relatively unknown and we don't have very good animal models yet to study it. we mentioned last time about

smoke as nicotine metabolites,nnk is a carcinogen, and nicotine binds to acetylcholi next receptors, and you remember akt, increasing survival of the cancer cells. they are then more difficult to kill.

and nnc forms dna aducts, cells do not undergo apoptosis, mutations accumulate. nyk can also cause akt correlation. lectureing to end this in about 30 minutes, and we're going to discuss ways about nicotine replacement therapy to

get people to stop smoking cigarettes. but you see there's a problem with that already, because if we're giving nicotine replacement therapy, the nicotine will still stimulate the cancer cells to grow. so if you do use nicotine

replacement therapy, you want to use it for the shortest period of time as you need to. and one interesting thing is we can tell who is a smoker and who is not because there's this one m metabolite which accumulates in the usual of patients who are exposed to

cigarette smoke. and so for many years the tobacco companies were resistant about the fact that their cigarettes were causing lung cancer and how did you know that a patient was actually a smoker? and then when they developed

this assa, whyy the cigarette companies got quiet because they had absolute proof of who had been exposed to cigarette smoke. and we note it's actually increased in nonsmokers who breathe in cigarette smoke, so secondhand smoke you can also

detect. one of the advantages of working in this field, i started working in it in the '80s, was that we had so many cell lines and so here at nci in the '80s, biopsy specimens from patients, these biopsy specimens were mechanically

disassociated, passing the cell suspension through steel mesh, and then the cells were cultured in a serum-free mulled medium. the normal cells died, but about one out of six of the biopsies specimens, small cell lung cancer cells would then

grow out and you have a group of cells from a particular patient. and so these lung cancer cells we see then that they need igf-1, binding to a receptor to stimulate growth. and one of the things we found is that peptide growth factor

found receptors and stimulated the growth. so over a -- in the '80s then, from 1982 to 1984, they established 31 cell lines, so we have a lot to work with in the lab. most cancers such as prostate cancer, you have maybe a dozen

cell lines, breast cancer a couple dozen perhaps, but for lung cancer we have hundreds of cell lines. and they were neuroendocrine they have high levels of bombesin pep sides. peptides. over a 20-year period, hundreds

of lines were established. we have lots of cells then to work with. and so then a goal became using animal models. one was using the a/j mice exposed to urethane that would get adenomas that appear as bumps on the surface of the

mouse lung. and so we found then that the adenomas, especially, would metabolize also lipids and enzymes would produce positives prostaglandin. here is an asay where we found we could inhibit growth with indomethacin or aspirin.

aspirin is used to prevent colon cancer. and the growth inhibition caused by the nonsteroidal antiinflammatory drug was reduced, it was also working through a receptor, not just an enzyme. here is using animal model,

whereby we have small cell lung cancers growing in a/j mice and when we inject the urethane it takes three months for tumors to form, and then by the fourth month there's about 20 tumors per lung, in the untreated animal, and in animals treated with indomethicin there was 20%

lest. if you didn't incorrec injectcarcinogen you didn't get any tumor. looking at the chemistry in these mouse lungs, we found then there was cox-2 immunostaining as indicatindicated by brown dots, in the adenoma and other areas of the lung.

this is the corresponding. the cox-2, there was intense staining in the bronchus, staining in u epithelial chris and adenoma also had immuneo-reacreactivity. cox-1 is a house keeping enzyme that's present in all cells. and this inhibits both.

with cox-2 we can induce it by adding egf, we get a substantial increase when we add egf, the antibody blocks the increase. and then the egf receptor can be cross-correlated. we mentioned previously that growth factors such as

transforming growth factor alpha and egf caused egf receptor correlation. in this case, the process occurs through a g-protein coupled receptor, and once the g-protein coupled receptor is activated it causes releasrelease transactivation.in

and it's ineubtd hade ineubthaded inhibited by a prostoglangin. cancer cells is can contrary will increase it. we added this drug, h-89, the effects were reversed. then the e-2 worked through amp. so the process is, we see,

cox-2 will cause lipid production, leading to pge-2 production, combines to receptors. it takes a few seconds to increase amp, an hour to cross-correlate, 24 hours to increase vegf production. when we look at transactivation

with the receptor activated that can activate, leading to alpha release, causing egf so this is a fascinating process then whereby one drug can cause all these downstream events and in turn cause correlation which will increase cox-2 production and this is a

cycle right here. so the traditional cox inhibitors can cause stomach ulcers and new dreg drugs were developed selected for cox-2 with minimal side effects. it is in clinical trials to see if it can function as a therapeutic agent in lung

cancer. so looking at genetic events we mentioned you have dozens of genetic events over a 20-year period and we talked about p53 and how it gets inactivated, and other things that get inactivated. p53 we mentioned plays a role

in the g-1 to s-phase and a-53 drives programmed cell death by apoptosis after dna damage, if it is mutated leading to cancer cell formation. you can have a variety of events going. this can occur in many lung cancer patients, and the rb pro

protein is absent or abnormal is 90% of the cancer patients but with rb we don't have any good drugs to treat, to have normal activity return. the fhit gene is located on chromosome 3p where a lot of lesions occur in lung cancer patients.

but fhit protein expression is associated with smoking and remains to be determined if phit is a tumor suppressor gene in lung cancer. bcl-2 suppresses apoptosis and inhibits responses to chemotherapy and radiotherapy. so one thing they are trying is

antisense to bcl2 in therapeutic trials. one company is promoting the use of antisense. all of these are trials. we don't have anything that works very well in small cell lung cancer. we mentioned there's loss of

chromosomes, especially in 3p, 4p, 4q, 5q, 8p, 9p, 10q, 13q, 17q, 22q. smoking takes so long for the tremendous genetic abnormalit, why. there's myc overexpression in 30%. one growth factor is stem cell

factor and c-kit a receptor andr and we'll be we'll be talking about bombesin. 3p delete is early, 5q, 13c and 17p deletions occur later. in lung cancer there's also micro satellite alterations, where there is a laddering of

sequences, may result from mutations in dna mismatch repair enzymes. and finally the myc genes are amplified. a more recent thing that they found is inactivation of the lkb1 inactivated in 50% of so we'll take a look at some of

the receptors. the big one is igf-1. this results in correlation, ultimately leading to erk and growth. so we had an antibody to the igf-1 receptor, it found the binding subunits at 90kdal. this alpha ir-3 functioned as a

physiological inhibitors. igf-1 works through akt signalling. so here is part two then, illustrating the receptor tyrosine kinase receptors. and then bcl-2 is then -- inhibits ability for activation.

so the growth factors increase survival of the cancer cells, so the cancer cells can undergo apoptosis. okay. scf and c-kit are present in approximately 70% of lines examined. we do have a drug for c-kit

stimulation, gleevav. we mentioned before that was used, and in high concentration can inhibit c-kit. so c-kit is a large protein, 976 amino acids, 520 amino acids. there's a 433 intracellular amino acid domain.

then in 1980, 1981, we found that high con tryinconcentrations were present in cancer cells. we made an antibody to neutralize the grow factor, you see in mice untreated as well as treated with control antibodies you get large xenograft, and they are small,

50 animals treated with 2a11. in the '90s we tried clinical trials, and unfortunately only one patient out of 13 responded to the 2a11, critica clinicaltrials were disbanded leading to the old saying of scientists have many times cured cancer in mice, but very few times in

humans. so this is why you do these pre-clinical studies, to get a drug that looks like it's going to be pretty good, but then in patients one in ten, one in 100 of the drugs that are developed and are effective in mice will actually work in humans.

so then we decided it was best to go after the receptor. and develop drugs for that. so here you see the receptor that's smaller, only 400, crossing the membrane seven times. the other only crosses once. and it binds to the

extra-cellular amino acid, note the intracellular amino acid are very few. here we only have 60. you need 400. what these receptors do is they work through signal transeption. aninthe female has twice asmany x

chromosomes as the male, are they more discuss accept it getting lung cancer? initial studies suggested that that may be the case. and here we see signal transdeduction, adding to cancer cells, the cells loaded with a dye, within 30 seconds

we see the floo flew flew thefluurescence increasing. we see an increase in second messenger production, in this case calcium, but it only lasts for a few minutes. it's a very, very fast signal. here is another way of looking at the calcium increase in cell

suspension, added peptide, within seconds calcium goes up and it stays up for a minute, and it starts to come down. and then we develop this one drug, a small molecule, you'll hear a lecture in october on small molecule inhibitors, this is one of them.

and you see that it blocks the ability of bombesins to increase. here you see the structure of the small molecule inhibitors, it's actually sort of looking like three amino acids, like a tryptophan and it looks -- this one looks more like a luceine

than anything else. so then the chemist and suit pharmaceutical firms are interested in making small molecules. we see they can block the g-protein coupled receptor but in the clinic now they use these especially for

reseptemberror tyrosine i am inhibitors. hirhere you goat get afour-fold increase and the small molecule antagonist about block it so the transactivation signal is lost. so egf receptor correlation is always upstream from erk, so

looking at that we see the ne.log increases, erk tyrosi they are revertible. if ththe drugs works for awhile but will fall off and get ma --sed. metabolized. growtif you combine them with gefitinib we see stronger

growth inhibition. it's only active on patients with egf reseptemberro receptormutations. we make it more potent by adding the g-protein coupled receptor antagonist. this is something we're looking at pre-critica pre-clinicallyand potentially it can make

patients more sensitive. and so we've already seen before how once you have the egf receptor cross-correlated you can go through the pathway, increasing survival, you can go through the pathway increasing proliferation. here we see t-i turnover

leading to increase and sark can stimulate a protease which combines to egf receptor, it looks complicated, but all of this occurs within one minute. it's very fast. then we see that a correlation within five minutes, going into the numbe nucleus to stimulate.

another way is through -- this increases motility anding migration. ultimately this leads to an increase in m met matastasis. we have much clinical trials in progress to improve the treatment of small cell lung cancer patients, but as of this

time we really don't have anything that's effective like the inhibitors. so the best thing, one time i did a test interview at an aacr meeting. we presented an abstract on nonsteroidal anti- inflammatory drugs reducing lung cancer

and so during the interview, it became very apparent what the reporters wanted to say, needed me to say, was that you took certain drugs it was okay to smoke so you couldn't get so they asked me then if i take aspirin, and i said, well, i can't, i'm allergic.

i get stomach ulcers. they all sort of started laughing. but then i said, the real thing is if you want to avoid lung cancer, just get people to stop smoking. and so now we have developed a very nice program in the u.s.

for this to occur, and one is nicotine replacement therapy, includes gum, nicorette, the patch, nicoderm cq, nasal spray, nicotrol. we mention you don't want to do this too long because nicotine will actually stimulate the growth of the cancer cells.

you want to use this and as soon as you can stop it, you want to stop it. another thing is there's very effective pills, one antidepressant is used, also sometimes on tv you see the commercials for stantix, which reduces smoking urge and

withdrawal symptoms. but smoking cessation, the best way is just to stop smoking, and this is how most people quit is they just go cold turkey, after gradual cigarette reduction. not everyone is successful the first time, so early failure is

quite common. but then ultimately, once you quit smoking, there's many beneficial effects. within 20 minutes after quitting, your blood pressure and heart rate decrease to normal level. within 12 hours, your carbon

monoxide levels in the blood return to normal. the cigarettes have a lot of co2 in them. within two days, your sense of smell and taste return. within nine months, there's a decrease in cough and shortness of breath.

within ten years, the risk of heart disease from stroke is normal. the risk of dying from lung cancer is reduced by 50%. so in the u.s. now we have 45 million smokers, and about 16% will die from lung cancer. so that's a big number.

force that's five million. but now there's 45 million ex-smokers. so that's sort of the good news, that the number of ex-smokers is increasing. and also the number of cancer survivors now is readily we now have over 12 million

cancer survivors in this country that are living. so that number is readily so we're on the right track in this country. we just have to continue to use less and less cigarettes, and then here is references that you can refer to.

and that's about it for me. thank you for your attention. are there any questions? [applause] so the small cell lung cancer was a problem in the 1980's, we had about 30% of the lung cancer patients dying from it. and then in 1985, they

developed what's called the high filter cigarette, the cigarette particles used to be very heavy, would drop down to the ground, and go deep into the lungs causing the small cell lung cancer, but once they developed the high filter cigarette, then the particles

were very small and so small cell lung cancer started to decline but adenocarcinoma of the lungs started to increase dramatically, and that's the big one now that we need to focus on. so we mentioned before about how cancer changes with time,

but in this case, you know, the best thing you can do really is to stop smoking and then the lung cancer rate will decline da mat el da. decline dramatically. we've done good in this country.

other countries are not so good. we're selling a lot of cigarettes to asian countries. and so china expects a dramatic increase in lung cancer in about 20 years, and they are working with nci as to what they can do to respond to the

potential epidemic of lung that they anticipate coming up. yes? [ inaudible ] yes, the electronic cigarettes are quite controversial. in theory, what they are supposed to do is just produce

less of the carcinogen, so they would be a safer cigarette. but, you know, no real clinical trials have been done at this point to say that they are entirely safe. and you wouldn't really know for 20 years. so the vote is still sort of

out on that. but what's good now is the spiral ct, and the goal for that is to detect lung cancer early, and so that's becoming more popular in this state. you know, that's a good thing. see, a general thing is the big pharmaceutical companies, they

don't want to have drugs for prevention. prevention because if a patient has cancer, and they give them a drug and the patient dies, they are not going to get sued. but if they go into prevention, if a patient then gets cancer they are going to want to sue

the drug company. so they don't want that, so a way sort of around that is using the device such as the spiral ct. and then if you can detect it early in stage one, the surgeon can go in, remove the tumor, and that's it.

-- a lot of lot of folks with hope with the spiral ct. >> we're pleased to have james gulley lecture today, he's it's director of clinical trials and deputy chief of the laboratory of the thermo immunology and biology, and he's in the center for cancer research, lecture

today positive toda prostatecancer, clinical update. >> thank you. it's a pleasure to be here. we have an active clinical program in positiv prostatecancer. i've been here 15 years at the national cancer institute. we're going to yo talk about

prostate cancer, first about giving you an overview about the disease, talking about local treatment options, and then talking about systemic treatment options. finally, where we're going from here. so as you -- as we go across

you'll see that we have a lot of data for some parts of prostate cancer and there's some big holes that we still have missing, like many cancers. let me give you a basic overview of the treatment now for prostate cancer.

when you're first diagnosed with prostate cancer often you have localized disease, and often you'll respond to local therapy, we'll talk about what local therapy options there are. eventually, about a third of men will develop risingd orso

tumor markers, t.s.a., following their local treatment and often will be treated with hormonal therapy at some point. eventually that hormonal therapy will initially work very nicely, but eventually, patients will start to progress despite the hormonal therapy.

then we'll talk about all of these other systemic agents that could be used in prostate cancer treatment. so what you also see is most of these patients are asymptomatic, even after they become metastatic, many patients will remain

asymptomatic until later on in the disease course. and this can drive some of our treatment decision points. so prostate cancer is the most common cancer among men, in the united states. most commonly diagnosed noncutaneous cancer.

at the the second most common cause of cancer deaths, as we'll see in just a minute. one in six men during their lifetime will develop prostate so what we have, you know, what, 40 people in this room? half men. so, you know, 20, we're talking

three or four of you will develop prostate cancer. so here you see the deaths for prostate cancer, starting with 1930 to 2009. here in 2010. what you can see is that lung cancer by far the number one cause of cancer-related

mortality, the prostate cancer is number two. you can also see that both -- well all three actually, lung, prostate and colon cancer, are the big three in men. they are all coming down, have been coming down since the mid-1990's.

that's good news. what are risk factors for development of prostate cancer? certainly age is a risk factor. as you get older, you're more likely to get prostate cancer. a family history of prostate cancer, so if you have one or two first degree relatives, you

have significantly increased risk of getting prostate first degree relatives are brother or father. geographic location, so it turns out that the united states and scandinavia have some of the highest rates of prostate cancer andations have

a lower incidence but when they migrate the incidence goes up. there's an increased risk of both lifetime risk and risk of death of prostate cancer for african-americans compared to caucasians. detection, prostate cancer can be detected based on one of

three things. you can be basessed o based onsymptoms. fortunately in the united states that's not what happens. symptoms happen, as i showed you before, really late in the disease course. most patients diagnosed in western countries are not

diagnosed based on symptoms. they are mostly diagnosed based on either psa screenings or digital rectal examination. what do i mean by whe when isay mean when i say digital rectal examination? with a gloved hand you can feel the prostate. take your thumb and forefinger,

what i want you to do is to pinch really tight like you're trying to hang on to a piece of paper or something thin. feel right here. thithis muscle part on yourthumb, when it's like that, that's what a normal prostate should feel like.

i want you to feel right over here on your knuckle. that's what prostate cancer feels like. when the doctor, when the physician, is feeling it in the digital rectal examination they are feeling for that. is there any area hard like

this? is it -- in what area is it? then they will go in and potentially biopsy that area to see if indeed there's cancer there. so that's one way we use to detect it. the other way is by psa, a

simple blood test that be done one serum from patients. now, you'll notice before the era of psa screenings, here is the number of cases per hundred thousand men. you cpn see right around here is when psa screening became widespread in the united

states. and all of a sudden you have a huge increase in the incidence of prostate cancer, the number of patients being diagnosed with prostate cancer. all the epidemiologists are saying, well, is this an epidemic of prostate cancer, or

are we just biasing it because now we can detect it earlier? there's a peak and it flattened out again. this is a by as, we were able to catch it earlier, and treat it, treat men with a lot lower burden of disease. the question is, did this

diagnosis of prostate cancer earlier using psa and digital rectal exams to screen, did that result in saving patients' lives? so there were two large prospective studies designed to look at this. there was the plco trial,

funded by the national cancer institute, the prostate lung colon and ovarian cancer screening clinical trial, and in that trial they enrolled about 75,000 men. and the men were randomized to receive screenings versus no screenings.

and after seven years, they looked -- they did a preliminary look at the data, and what they found was that in the screenings cohort, 50 men died of prostate cancer verses 44. it was a complete wash. very few out of the 76,000 men

had died from the prostate so perhaps it's too early. or perhaps there's not enough events to really get any inclusion, but it didn't seem at least in the early look, and we're going to talk about what seven years of prostate cancer means in a little bit, but at

least in the early look it didn't look like there was a big benefit to doing screening. now, there's a trial done in europe, it enrolled more than double the number of men, and they looked at those men by screening versus no screening. and they -- about the same

amount of time, a little bit longer follow-up, nine years, there was a 20% reduction in the prostate cancer mortality. so one thing that one might say is, well, this is certainly a different patient population than the u.s., certainly they used the psa screening, it's

not as widely used there, so these patients may have been further advanced. interestingly, about half of these men that were randomized to the no screening arm got their psa test done anyway. at their local physician. so it's just too widespread use

here, maybe that diluted it. we just don't know yet. the full picture hopefully will be coming out later. we'll talk a little bit more about this when we talk about other trials too. so when you are diagnosed with prostate cancer then, what do

you look at to look at the prognostic features. the pathologist will assign a gleason score. that's looking under the microscope and seeing does this look aggressive or not? the more aggressive it looks, the higher the number.

and they will take the -- they will give it a score of between 1 and 5. and they will take the most common area, the most common pattern that they see, and then they will take the second most common pattern, and together that will be the gleason score.

so you can get anywhere from 2 to 10 out of 10, although right now it's very uncommon to see anything less than a gleason 6 tumor because of the changes in the gleason grading pattern. so a primary pattern 3 is usually what you get a 3 for or a 5.

gleasonyou'll get a gless score between 6 and 10. we'll talk more about that in the clinical trials. staging for prostate cancer, so there have been some interesting staging changes in prostate cancer recently, it used to be just the anatomic

staging but now we've added in gleason score and psa. so that stage 1, you almost never see anymore because your psa has to be low and gleason score has to be low, this is probably incidental tumor. some people argue, and there's editorials, saying we shouldn't

call this cancer at all. we'll come back to that too. and then as it becomes palpable, or locally advanced, or met static metastatic, thestage goes up and positive know prognosisbecomes worse with increases in stage. so prognosis, we talked about this a little bit.

prognosis is based in part on the psa diagnosed, how high it is, the higher the psa the worse for the patient. the percent of tumor in a biopsy specimen, so if you get more than 50% of a core being positive, that's a high amount of volume of tumor.

the number of positive biopsies, typically a 12 core biopsy, so you get 12 different areas of the prostate that are sampled, and if you get two or three of those positive, that's starting to be a large amount. if it's more than half of the biopsy sample that's positive

that's high volume disease. gleason score, all of these are important when looking at prognosis. you can take the factors and plug them into different tables, nonograms online and get the predicted rate for having the disease confined to

the prostate, or having it be outside of the prostate involved in the lymph nodes and have the prediction for how the patient will do can surgery or radiation therapy, how the patient would do in terms of progression for survival, the probability.

now, the rest of the talk we're going to talk about various different treatment modalities, so for patients to have a life expectancy of less than ten years, or especially those patients who have a low gleason score, so a gleason 6 tumor, they may be candidates for

active surveillance. what do we mean by active surveillance? we mean we'll just continue to follow the psa and perhaps do additional biopsies, to see that the gleason score is not getting worse. in part, the data is based on

this study. this is a study that showed that men that were either older or men that had especially low gleason score tumors, those men actually did really well in terms of outcome. what you're seeing here is this is a box, you can see pro

portioproportion of patientsalive, 100% to 0%, shaded in gray is the overall survival. the dark line is the death due to prostate cancer. you can see that if you have a gleason score that's, say, 5 or 6, you have very few deaths proportionally from prostate

most of the men that are going to die over this, and this is a 20-year follow-up time, are going to die from other causes besides prostate cancer. if you get a gleason score of 7 or 8, you have a significant likelihood of dying from your prostate cancer, especially if

you are younger. you know, 90% of patients that die, die from prostate cancer. if they are not treated up front. so bottom line, low gleason score, you may not need to do anything. older age, even with a more

aggressive tumor, such as a gleason 7 tumor, if you're 70 to 74, you only have a 40% chance of dying from prostate cancer and 60% chance of dying from something else. so if you decide, well, you want to treat, but perhaps the patient is -- either has

survival of expected less than 10 years, you might want to treat with deprivation therapy. patients that, a, are not good surgical candidates, or don't want local therapy, or patients aggressiveve more aggressive disease but may have a lot of heart disease maybe and

therefore not good surgical candidates. this is a study looking at endrogen therapy, hormonal therapy, later on when the patient developed progressive disease. what you can see, there's a thousand patients enrolled,

hazard ratio was 1.25 favoring the use of early hormonal therapy, about a 25% improvement in survival. and interestingly, most people would say that, well, you start hormonal therapy earlier, you just are burning that bridge. what was interesting was that

there was no earlier time until what we call castration resistance prostate cancer where they progressed on hormonal therapy, whether you started up front or waited to start it. so it probably was, if you waited to start it, you

probably developed such a bulk of disease that when you came in with a hormonal therapy, it blew through it more quickly. survivalse specific file was was not different even though overall survival was, overall survival is the primary end point.

for patients with a predicted survival of ten years or more, that is actually most of the patients that we see, with prostate cancer, even though median age is 71 years old, these are the treatment options. yooptions.

you can do surgery, surgical remove, external-beam radiation therapy or brachyperp. first, surgery. so as i mentioned, surgery, radical positive thaprostatectomy is surgical removal, done with a variety of different approaches.

the most common side effects are actually impotence, which we'll talk about, and incontinence. let me mention before we talk about side effects, let me mention a recent trial that was published a couple years ago, 2011, in the new england

journal of medicine. in this trial, patients were randomized to receive surgery, versus just watching the and not doing surgery. you can see that there was an improvement in survival, if you got the surgery versus this watchful waiting, which

basically was treating the patient later on with a variety of treatment options. this was the overall group of but what's even more interesting, i think, this subgroup analysis, that is if you just see older men, men greater than or equal to age

65, we see there's no difference here in either deaths from any cause, death from prostate cancer, or time to met' ma metastasis. in younger men you see this splitting the curve that there's less competing causes of mortality, the less people

are going to die from their heart attack or stroke, and more people are going to be -- end up being affected by this. it appeared that the majority, if not all of the benefit for this surgery, was in the younger patient population. we'll come back to that in

another trial where we see similar type of trend. right now we'll come to it, so this is a trial that was just published late last year, less than a year ago, and this was the pivot trial. this is the prostate intervention versus observation

trial. what was interesting about this trial, you see there's really no big difference between observation and radical prostatectomy. if a patient is getting no surgery, and this is a u.s. trial, the other trial was a

european study. so less of a difference here in the u.s., perhaps because we're finding the patients earlier, we're doing the psa screening, and that would suggest that maybe what we need to be focusing on is who has that lethal phenotype, patients that

have the disease that really need to be treated. maybe we're finding too many patients here in the u.s so what you can see in this pretty busy plot, i want to point out, this is the same thing for both of these. overall survival, the primary

end point, you can see those men had a psa greater than 10, the more advanced disease, those patients had a stat statistical benefit from surgery. conversely those men with the low risk disease, usually low gleason and low psa, and low

stage, they appeared to have no benefit, maybe even slight detriment, from getting surgery, the intermediate high risk appeared to have the benefit of surgery. what we need to focus on, i think, is patients that have the alit lethal phenotype,maybe men

of those that have less advanced disease can be watched. there's lots of studies, it's actually changed the paradigm -- arepatients are dealing being treated in the u.s let's talk about radiation therapy.

so what is external-beam radiation their? radiation therapy? radiation from outside the body. a variety ofom a "variety" of studies. there's a new -- ten years ago this was new, intensity mod

lated radiation therapy can allow for a high amount of radiation directly to the tumor sparing most of the normal tissue. the most common side effect with radiation therapy also includes impotence and rectal irritation.

so like surgery, impotence is a big issue. so just to show you here the radical -- sorry, radiation therapy in the lighter gray and radical prostatectomy in darker, you can see here both of them are pretty bad overall when it comes to impotence.

there's a quicker decline with surgery, and then there's a plateauing out that takes longer to get there, to come down, with the radiation but they both end up with about 50% of the men having decreased ability to get or maintain an erection that is sufficient for

vaginal penetration. why is that? so turns out that the neuro vascular bundle that runs right next to the prostate here, this is the prostate right here, enervates the penis and allows for erection. if you were to come in with

surgery, and cut out this prostate, that you would be interfering with that, especially if the tumor is near this part of the prostate. certainly the same thing with a radiation, where the radiation goes through there too. so how do they do in terms of

incontinence? this is urinary incontinence, dribbling or some leakage of urine? you can see that it's much worse than surgery than it is for radiation but they both take a little bit of a hit and how about for bowel bother?

if you get irritation, it's worse with radiation, you can have patients that have multiple small bowel movements every day, it's not as bad as incontinence or impotence. and brachytherapy, implant of seeds in the prostate, you can see the pelvic bones here, the

prostate has multiple seeds implanted, radioactive, permanently left in the prostate that give off radiation over a erred pooh of a period of a month. after that the radiation is gone. the nice thing for patients is

this procedure is a one-day procedure. it can be done on an outpatient setting, and doesn't require them to be hospitalized like surgery does, or doesn't require them to come back monday through friday for 15-minute likes external beam

radiation for up to 8 weeks. but really should say brachtherapy is indicated for low risk or perhaps intermediate risk tumors. high risk there's no defined role for brachytherapy, it certainly by itself. it can be combined with special

beam radiation. now how about bowll locallyadvanced diseases? perhaps you could do conservative management. for patients that elect radiation therapy, one can give radiation plus hormonal therapy and there's also data for

surgery, hormonal therapy with let's talk first about the radiation therapy. i'm going to give you one example, because of time of a clinical trial. this was the first clinical trial showing an improvement in overall survival, if you

combine hormonal therapy, endrogen deprivation therapy this trial was small with at least four trials since, randomized trials, that have shown much the same data. and there was improved outcome when you gave the combination, both in terms of local control

of the tumor, so less symptoms, locally. met'asasis free survival, and most importantly, overall survival. 62% versus 78% at five years, this is highly statistically significant. let's talk about surgery, there

have been a variety of studies looking at hormonal therapy, and there's been nothing that has improved -- has had an impact on clinically significant end points except for one trial in which patients with lymph node positive disease were at time of

surgery, and this is just microscopic disease, so at surgery they took out the prostate, they took out the lymph nodes, and they went carefully, the lymph nodes were not enlarged but they carefully looked at this under the microscope and found there were

some cells of prostate cancer within the lymph nodes. they found that if you put those patients on hormonal therapy right away, those patients actually lived longer than patients who didn't get the hormonal therapy right away.

and this trial was closed early because of the improved overall survival that was seen. 98 patients were enrolled, 12 years of follow-up, 17 of 47 patients died in the immediate androgen deprivation therapy, and only 28 out of 51 died in delayed therapy group.

this was a hazards ratio of 1.84. so 84% increased risk of death. in the delayed group. now, i mentioned, it was not fully enrolled and this probably is worse outcome than you would expect for this group of patients, so there are some

people that question this data but it remains the best data to date. the only randomized trial to date in this patient population. so it is considered standard of care. how about patients that undergo

surgery and now are found to have still disease left behind? surgical margins are positive, a pathologist sees the cancer going into the edge of the tissue that's obtained. turns out these patients are also benefited if they start hormonal therapy early.

this is a trial enrolled about 425 patients, they had positive margins, but no lymph nodes that were positive. if they started hormonal therapy right away, sorry, not hormonal therapy, radiation therapy, right away, so radiation to the local area,

you had improved survival compared to observation, statistically significant. this is at ae median follow-up of 12 1/2 years, let's talk about patients, we talked about local therapy, how about patients whose psa starts to rise, a issued tha -- a thirdof patients

not cured by local therapy. what happens with those patients? what are the actions for those well, this rising psa could be due to local disease, right there at the level of the prostate, and maybe those patients could get radiation

still if they've had surgery before. or it might be metastatic disease and that could be metastatic disease we can see on scans or perhaps not. options include local therapy, hormonal therapy or following the patient.

it's difficult to look at this group of patients and say if it's going to impact their overall survival. that's because of this data this is a trial where about 2,000 patients with radical prostatectomy were followed, and 304 of them experienced a

psa relaps, rising psa. of those 304, 103 went on to develop metastatic disease. based on this data set, this data set is from hopkins, a single institution where were treated by a single surgeon, none received hormonal therapy before having clinical

metastatic disease, it allows for looking at the natural history of prostate cancer. the median time from psa elevation to metastatic disease was 8 years. that's a long time. median time to death after that was an additional 5 years.

you have surgery here, average of 2 years before the psa started to rise, average of additional 8 years before they develop metastatic disease, and average of another 5 years before they die. now, a lot of these patients have low gleason scores, they

were not very aggressive clinically. this is kind of changing as we are moving into the era where we're doing surgery on these more aggressive prostate cancers and leaving the gleason 6's to just watch and follow. we'll see how this evolved over

time. but that becomes difficult then if you have that long of a follow-up, are you really going to impact survival? perhaps some patients, especially if their psa is not going up quickly, you can probably just sit on these

patients and watch and wait and wait and hopefully not have to do anything for years. once somebody develops metastatic prostate cancer, really that's where a lot of us have our -- that's the trigger -- hormonalart har money it typically spreads to bone

and lymph nodes did yo but cango anywhere. only 40% of patients with metastatic prostate cancer have soft tissue disease. the rest of them have bone only that is disease that is just in their bones. that is not -- we can't really

measure how big those lesions are based on the bone scan. it's difficult to do our traditional studies where we shrinkage of tumors.of the psa books a good marker to see how a patient is doing in terms of therapy. let's talk a little bit about

the cornerstone for treatment prostate cancerroperty taste that led to a nobel prize by dr. huggins here. basically what he showed was that in patients with advanced prostate cancer, he took a large number of patients that had advanced positiv prostatecancer,

decreased testosterone levels, using sin the syntheticestrogen, and they got better quickly, the tumor markers, that was before psa had been identified, but the tumor markers came down significantly. what he did was something that probably wouldn't pass our

irb's today, but this was in the days before there was al reviewnt institute jag board authority. he gave the same men back testosterone, their symptoms came roaring back, the pain they were having became much worse.

he showed very convincingly that testosterone was very important in driving prostate cancer growth and symptoms. and based on that in 1966 he won the nobel prize in medicine, or shared it. let's talk about hormonal therapy, what is it?

well, this is a representation of a prostate cancer cell or prostate cell. you see the sig cytoplasm, thenew nucleus. the testosterone comes into the cell, within the cell testosterone is converted to d.h.t, and then it binds to the

androgen receptor, in the cytoplasm of the cells. once you bind the androgen receptor, you dimerize, you get heat shocking chaperones that will bring the androgen receptor into the nucleus, and it will bind to androgen response elements and drive out

transcription and translation of the cell and so you'll get okay? this anabolic process is driven by this testosterone, so by knocking out testosterone, you're going to then inhibit all of this pathway and inhibit transcription translation, et

cetera. so there are several different ways we can knock out the testosterone by directly lowering the amount that's made in the body, or we can actually interfere with the pathway by hitting the androgen receptor. testosterone-lowering therapies

depend on the fact that the hormone made in the pituitary can be lowered. if you give either a gnrhing agonist or antagonist you can decrease the levels of testosterone, because gnrh is released, if you give an agonist it's going to be --

you're going to get transient increase in testosterone levels before they drop to nothing. there's only one approved antagonist, and it requires monthly injections rather than injections every three monks, with the gnrhing aist in. orchiectomy is another option,

removal of the testicles, where you make 90% of the testosterone found in the body. so side effects of hormonal therapy, androgen deprivation therapy, there's a long list. but the main ones that you will hear men complaining about, include the decreased libido,

decreased sexual drive, erectile dysfunction. hot flashes are a big one. it's similar to like when women are going through menopause. very similar in terms of intensity and type of symptoms that they get from the hot flashes, and it's very similar

in terms of the pathophysiology, we treat it the same way we treat him going through hot flashes, similar types of therapies can be used. you can get some increased fat deposition and decreased muscle, you can get a little bit decrease in bone mineral

density like when women with going through menopause, they can be in acceleration of bone loss. and you can potentially get an increased risk for diabetes and there's some controversy surrounding whether or not there's an increased risk for

heart disease also. the other way we with interact with the an androgen signal pathway is broo blocking the receptor.error, thosthose of these drugs willbind to the androgen receptor, the earlier classes of drugs just bound to it and prevented the

testosterone from binding to a certain extent. some new agents, what we're tall about, their benefits in just a minute. so all of them have a similar mechanism of action. they bind to androgen receptor and can decrease the go signal

for the prostate itself. there's other hormonal agents. ketoconazore has beeole hasbeen used until recently abirateron was recently approved, increasing the synthesis of adrenal male hormones, we'll talk about that in a little bit. so now let's move to metastatic disease,

treatment options for a patient with metastatic prostate cancer, who now started to have symptoms. until 2004, really nothing was shown to improve survival in men with prostate cancer that had me metastatic disease, very disappointing.

some aeurbts wer agents wereapproved based whatcreasing symptoms, that they showed was if you gave this older chemotherapy drug, you could actually improve the quality of life of men for a longer period of time than if you just gave the bread in glucocoticoids such as bread in

this season. prednisone. this became the standard of scare and helped men get through some of the symptoms they were having. so because of that, it was used as a standard agent compared with a newer agent, also known

as docataxel. all of the groups got prednisone to even that out. what they found was that if you give the docataxel every three weeks you get an improved survival, the weekly docetaxel fell in between. there was a 12 r. ar atwo-and-a-half

month increase in survival, 22% reduction in the risk of death if you got docataxel. i should also mention that that may be an underestimate of the true benefit, because patients who received it at progress with allowed to get the docataxel, and half did.

cabazitaxel appears to have activity. they looked at 750 men with metastatic prostate cancer who progressed after receiving docetaxel. what they found was there was more fox es city in the -- there was more toxicityx is

but there was an improvement in you can see here about 30% improvement in the mortality compared with -- or overall based on this, the f.d.a. approved this in 2012. let's talk about abiraterone, also recently approved in 2012. what you can see here is that

the way it works is by decreasing the synthesis of the male hormones, androgens, both within the adrenal glands and something we've identified in the last three or four years is tumors have enzymes that can make the androgen themselves. positivthey are making theirown

gasoline, they are fueling their own growth. this can lower the testosterone levels to very low levels in the serum, but they can lower the intracellular levels substantially, it appears in patients treated with just standard hormonal therapy, the

intracellular androgen levels can still be relatively high. so in this publication, the new england journal of medicine, 2011, you can see the overall survival was substantially better, you see a 35% reduction in risk of death, and this is following chemotherapy, the

time to psa progression was also longer, an ten versus six months, and progression survival fiving th better withthis versus placebo. the f.d.a. approved it for prostate cancer. now we'll talk about the final hormonal therapy agent that i

want to mention. this is another agent that is an androgen receptor antagonist recently approved based on improved overall survival in the last, as i'll show you, in the last you few years we've had a large number of approvals.

this is an androgen receptor antagonist with a high affinity for binding to the androgen receptor, bicalutamide, 80% of the market share before this, you can see much better with mdv 3100, not as good as the gold standard, but you can see there's less likelihood of this

androgen receptor complex being it doesn't bind to the androgen response element and can't initiate transdescription and translate, where with bicalutamide you get some, you what did this drug look like? early on in the initial phase one and phase two studies, what

you saw was there was a substantial proportion of patients that had decreases in psa better than you would see with chemotherapy, for instance. you see a little over half of the patients, chemotherapy naive, or after had decline in

psa. so in another landmark article published last year in the new england journal of medicine you see there was improvement in overall survival and radiographic progression-free survival if you received this. this was better than the other

data. the last approved -- well, no. we've got two more approved agents. the last agent that we're going to talk about, patients with metastatic prostate cancer, as i mentioned, they often have disease that is predominantly,

if not solely, visible in their bones. you can see this is a patient, this is a bone scan, you can see multiple lesions on the skull, the white areas represent prostate cancer lesions, here is the rib. here is a frontal view.

there is a bone-seeking agent that was just approved this year, called radium 223, and alpharad,n waden was a name itused to go by. now it's xopiga, with an x. it'if you look at the periodic table, it's in the same row as calcium.

this radium looks to the body like calcium, so anytime that there's active ongoing turnover of bone, it's going to pull in this radium in it there, and in these osteo blastic lesions that prostate cancer tends to have, there's lots of ongoing active turnover incorporation

of radium into the bone and because it's an alpha emitter it will go and actually kill the cells it comes in contact with. so again this is published in the new england journal of medicine just this year, a few months ago.

you can see overall survival substantially better than placebo, that's a very good clinical end point. also substantially better. so in the final few minutes we'll talk about therapeutic vaccine. now, this happens to be the

area that i like the best. the area that i'm involved in, in my research here at the intramural program. there is one approved therapeutic vaccine for prostate cancer, an and that is know as provenge, the trade name.

the idea behind this and all therapeutic vaccines is develop an immune response whereby the patient can recognize and attack the tumor. the immune system can recognize and attack it. how do they make this particular drug?

well, take a patient, that patient undergoes removal of blood, it takes and they spin down the blood and take out white blood cells and give the patient everything back, mass plasma, platelets, et cetera. they take -- they target what's prostatevirtually all positive

cancer cells and have a fusion. they put that in with the cells and that causes these white blood cells to become activated, and the androgen presenting cells within that can become activated, generating an immune response. process takes three days and

the process is repeated every two weeks for a total of three times, so over a erred pooh of month, that's an entire treatment course for a patient. that's complicated, but there was a large face phase 3study, patients received either this vaccine or placebo, and the

primary end point was overall you can see that patients that received the vaccine actually lived longer. there was a 22% reduction in the risk of death and the improvement in survival was four months. so based on this, the f.d.a.

approved this. what we're working on here is a different strategy. rather than going through all the logistical complicated processes of being apharesis, we're taking an off the shelf approach. we've designed, engineered, a

vector. psa found in virtually all prostate cancer cells as well as jeeps fo genes for othermodels system the immune sis step revved up, putting into a viral vector and all we can do is take that out of the freezer, thaw it and inject it like a

flu shot. it's simple but imunologically advanced vaccine. designed for the impact trial, the provenge trial, vaccine versus empty vector, the progression for survival was the primary end point. overall file wa survival wasthe

secondary end point. you can see a nice improvement in overall survival, 8 1/2 months, 44% reduction of risk of death if you receive the so this has led to an ongoing phase 3 study. but what was interesting between -- with this study, and

with the provenge trial, what they had in common, there was no improvement in progression-free survival. the survival, overall survival, was clear and significant, clinically meaningful, but the progression-free survival, the time until the patient's

disease started to get worse, was not any different between the two arms. there was no substantial decrease in psa like you saw with the others. i think it's important when we think about what might be going on here, to think about the

differences between therapeutic vaccines, immuno therapy and conventional therapy. first of all, cyto toxic therapy targets a different environment. immuno therapy targets the immune system which in turn targets the tumor.

perhaps in part because of this you may see a delayed response. in fact we see that often where we patients getting some newer immune checkpoint inhibitors have disease that gets substantially worse before going down to nothing. with therapeutic vaccines you

expects to see a memory response, that's in fact one of the goals, but you don't expect to see that with conventional conventional therapy's often limited by fo toxicity. perhaps in part because of the delays but pr prolong responseyou kinetice a different ken itic

profile. we looked at data. extremes we found what we came in with our most aggressive chemotherapy regimen, what you see is a dramatic decrease in the tumor volume in the majority of patients treated, remaining down for a variable

teared of time. when they started to progress you could accurately define when the patient was going to die and that growth rate was pretty much identical to the growth rate in the study. when you came in with immunotherapy you didn't see

this big decline in the tumor growth rate. sorries thsorry, the tumorgrowth rate. you sawe an eventual slowing down that could increase survival, brings to mind the tortoise and the hare, slow and steady win the race. one example of a patient that

with treatment with prosvtvac and early on when they were diagnosed, the rate the psa was going up at, they had surgery, it came down nicely. it's going up at the same rate eventually they had vaccine, you can see the psa continues to go up and comes down

beautifully but when it starts to go up after the three vaccines, it's going up at a slower rate. they got irb approval to give the patient another three vaccinations, and you can see here it appears to have flattened out again.

in follow-up data from that, that will be coming out this year, it's in press right now, the psa dropped down to less than 4. how do we put the vaccines into juxtaposition with the other approved therapies? well, you have the chemotherapy

vaccine, hormonal therapies, and this was just approved this year, all the aeurbt agentsapproved recently. you can see the decrease in the hazard ratio, which is a decrease in risk of death. so we get a 24-37% reduction of risk of death.

improvement in survival between 2 1/2 and 4.8 months, wit or44% reduction in death, 8 1/2 month improvement in survival, based on phase 2 data. there's a phase 3 trial going on right now. what i would also point out is that the number of patients

that have to stop due to adverse events is low with the vaccine compared with the other therapies. but also the portion of patients with declines in psa, very low in the vaccine compared to the other therapies, as we already know.

so based on this data there's an ongoing phase 3 trial, that will enroll 1200 patients looking it's a overall what we've talked about is treatment for localized disease, radical prostatectomy, radiation, brachy therapy, hormonal therapy, standard of

care to combine with radiation therapy following radical prostatectomy and in patients with metastatic disease as prime airplane therapy. primary therapy. we talk about vaccines, patients with more advanced or perhaps reserved for

symptomatic prostate cancer. we talked about these brand new agents, and this radium 223. and finally what we didn't talk about was zoledronate, they do not improve survival but can decrease of chance of them skeletal relatedal related events.

thank you and i would be happy to answer any questions. a good question. the question was can you get vaccinated for prostate cancer before you're diagnosed as a preventive?t i we think about flu vaccines or hepatitis to prevent you from

getting hepatitis or cervical cancer vaccine, the hpv vaccine that hopefully is going to eradicate cervical cancer as we know it now. yes, in theory, yes. in kneer theory they could workto generate a response to decrease the chance of getting prostate

i don't know that we are ready yet to do a trial of that magnitude that would prove effectiveness of this. it's going to take a vaccine like what we have that should be a lot cheaper to do, i should just mention there has been been some controversy

because this vaccine, because of the logistical issues associated with it, it is very costly. it's about $93,000 for a treatment course. so that works out to $31,000 per vaccine, you get three over the period of one month.

other questions? i saw a hand. right. it's a good question. so could you treat benign prostate conditions with this? or could you treat pre-cancerous lesions with somebody that's at high risk

for developing cancer. the answer is potentially we actually are talking with the prevention, prostate cancer prevention program, to see if perhaps we can use this in patients, we might actually try it first in patients who are candidates for active

surveillance. and then see if we can come up with parameters that would enable us to do a larger study, the parameters would be can we take and decrease the pro poergs oproportion of patientsthat go on to get surgery or if we can prevent them from having to go

through a morbid procedure, radiation or surgery, that's a good thing. tapperhaps we could bygenerating immune response that could wipe out some bad acting cells we could prevent or delay that. that would be a good thing. foror other benign conditions,

potentially one could use this. you know, could you one day be able to get a vaccine that is potent enough or mod light modlate the immune system for a removal of the prostate rather than by surgery, you know, it's not -- you might say that'sen science fiction.

stay tuned. some things we have going on are really looking interesting. so potentially there's certainly patients that get organ transplants. we know the immune system is capable of annihilating that organ.

how to turn on the immune system and get it to react to that, i think we -- i think in the next decade we could make significant advances towards that. so two things. the kotaconozole is f.d.a. approved for fingernail fungus,

other fungus. it's the same mechanism used to fight fungus, so it's a sterol, the steroid enzymes are hit, but a much higher dose than we use to fight fungal infection. at the higher doses, it affects a lot of the adrena adrenalsteroid synthesis, and by doing show

shuts down several things. it can shut down not only the moregen and other sex more gland too.enals grand and because of the issues with that there's a lot of drug-drug interactions, so probably soon to be relegated to the history books in the treatment of

prostate cancer, because effectsmuch fewer side with others, if you add it to patients on abutarone there's less drug interaction and survival, never known fo shownfor. r. ketaconozole. thank you very much.

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