>> GOOD AFTERNOON.

UNFORTUNATELY ONE OF OUR

SPEAKERS FOUND IT UNABLE TO BE

HERE TODAY SO I'M GOING TO FILL

IN AS THE HEART SURGEON.

SO THESE ARE THE TOPICS WE'RE

GOING TO CONSIDER.

A FEW THINGS I WOULD LIKE TO

BRING TO YOUR ATTENTION.

WHY IS PRIMARY CANCER OF THE

LIVER DIFFERENT FROM ALL OR MOST

OTHER SOLID TUMORS.

WE TEND TO LUMP ALL THESE THINGS

TOGETHER IN THINKING ABOUT

MECHANISMS OF TUMOR FORMATION.

BUT THE REASONS ARE LISTED HERE.

FIRST OF ALL, THIS IS A BIG

PROBLEM.

AND THE NECESSARY DENSE

CONTINUES TO INCREASE WORLDWIDE.

SECONDLY EXPERIMENTALLY AND

CLINICALLY, WE KNOW THE EAT

TAWLG OF MOST -- ETIOLOGY OF

MOST CAUSES OF PRIMARY CANCER OF

THE LIVER AND EXPERIMENTALLY WE

UNDERSTAND THE PATHOGENESIS IN

SOME INSTANCES AND ACTUALLY IN

GREAT DETAIL.

RESPONSE TO PREVENT 50% OF

PRIMARY CANCER OF THE LIVER, BUT

THE OBSTACLES ARE THAT SOCIETY

AROUND THE WORLD IN PARTICULAR

DOESN'T WANT TO INVEST IN THE

MEANS TO DO THIS.

WHERE THEY HAVE, THE RESULTS ARE

DRAMATIC, WHICH I'LL SHOW YOU.

NOW OF GREAT INTEREST AND

BIOLOGICAL CHALLENGE,

PARTICULARLY TO BASIC

SCIENTISTS, THE FASCINATING

THING THAT PRIMARY CANCER OF THE

LIVER IS USUALLY ENTRANCEALLY

RESISTENT FROM ALMOST ANY

ANTI-CANCER DRUG THAT'S USED.

NOW MOST CANCERS BECOME

RESISTENT AT THEIR PARYK AND

HAVE BEEN TREATED

PARTICULARLY -- AT THEIR PEAK

AND HAVE BEEN TREATED

PARTICULARLY WITH SINGULAR

TREATMENTS AND GIVEN IN

COMBINATION WITH MULTIPLE ONES.

BUT PRIMARY CANCER ON THE LIVER

HAS A BIT OF A UNIQUE FUTURE

THAT IN THE VERY BEGINNING

BEFORE ANYBODY RECEIVES ANY

ANTI-CANCER DRUG, THEY SHOW

MANIFESTATIONS OF MULTIDRUG

RESISTENT.

THAT PRIMARY CANCER OF THE LIVER

IS A SILENT KILLER.

IN MOST PATIENTS, PARTICULARLY

IN THE EARLY STAGES WHEN

SOMETHING CAN BE DONE ABOUT IT,

THE PATIENTS ARE ASYMPTOMATIC.

AND THE DISEASE PROGRESSES AND

PRODUCES SYMPTOMS ONLY WHEN THE

TUMOR INVADES SOME CRITICAL

STRUCTURE.

WE'LL TALK A LITTLE BIT ABOUT

THAT.

THERE ARE ALSO TECHNIQUES FOR

SCREENING THE DEVELOPMENT, WHO

GETS PRIMARY LIVER CANCER AND

SCREEN THOSE PATIENTS,

PARTICULARLY BY IMAGING

TECHNIQUES AND ZONOGRAPHY.

BUT WHEN YOU'RE TALKING ABOUT

THE LARGE POPULATIONS THAT WE'RE

GOING TO ENUMERATE, SCREENING

ALTHOUGH IT MAY BE EFFECTIVE TO

AGREE IT'S NOT VERY PRACTICAL.

AS YOU'LL SEE AT THE MOMENT,

THERE ARE NO CONSISTENT MARKERS

THAT MAKE A DIFFERENCE.

NOW CURIOUSLY, THE PEOPLE CAN BE

CURED IF IT'S DISCOVERED THAT

THEY HAVE SMALL TUMOR, AND THEIR

LIVER IS TRANSPLANTED.

THAT COSTS ABOUT HALF A MILLION

DOLLARS AND IS NOT A READILY

AVAILABLE EVENT.

SO THIS IS SORT OF A PANOPLY OF

TOPIC THAT I'M GOING TO COVER

AND COMMENT ABOUT, SHOW YOU SOME

DATA IN THE NEXT HALF HOUR.

AND THESE ARE THE THINGS THAT

MAKE PRIMARY LIVER CANCER QUITE

SEPARABLE FROM MANY OF THE OTHER

SOLID TUMORS.

SO I THOUGHT WE OUGHT TO BEGIN

AT THE BEGINNING WAS PROBABLY

NOT MANY OF YOU ARE FAMILIAR

WITH THE MORPHOLOGY OF THE LIVER

SO I THOUGHT I WOULD SHOW YOU

WHAT A NORMAL LIVER LOOKS LIKE.

IT LOOKS LIKE A FOOTBALL AND

IT'S UNDER YOUR RIGHT RIB CAGE.

AND THE MORPHOLOGY IS SUCH THAT

IT'S PREDOMINANTLY A VASCULAR

ORGAN.

THE PREDOMINANT CELLS ARE THE

HUH MATT SITES WHICHEPATOCYTES WHICH ARE R
ATHER

DULL LOOKING AND AFTER UNDER

GOING MITOSIS ONCE A YEAR.

THEY FORM THESE LONG CHANLTDZ,

CORDS WHERE THE BLOOD FLOWS IN

ONE DIRECTION FROM THE INFLOW

SIDE, FROM THE INTESTINE AND THE

ARTERY, TO THE OUTFLOW SIDE

WHERE IT GOES BACK UP TO THE

HEART.

AND THE BIODUCTS ARE REPRESENTED

AS BETWEEN THE ROWS OF

HEPATOCYTES.

AND THAT'S THE STRUCTURE.

IT'S NO WHERE NEAR DRAMATIC AS

LOOKING AT A BONE MARROW WHERE

YOU SEE CELLS IN MULTIPLE STAGES

OF CHANGE.

NOW THIS IS WHAT HAPPENS WHEN

THERE'S A CANCER.

THE SOLID LIVER HAS MULTIPLE

AREAS THAT ARE SLIGHT LY WIDER IN

COLOR AND THEY REPRESENT PRIMARY

CANCER IN THE LIVER FOR REASONS

WE DON'T UNDERSTAND IS

FREQUENTLY MULTICENTRIC.

IT DOESN'T ALWAYS JUST BE ONE

THING.

THERE MAY BE ONE AREA OF ONE

LOBE AND ANOTHER AREA OF ANOTHER

LOBE.

WE ONLY HAVE SOME VERY LOOSE

IDEAS ABOUT WHETHER THOSE OF THE

SAME COLONIAL TUMORS THAT ARE

PRESENT.

THESE SOME EVIDENCE TO SUGGEST

THEY ARE.

AND THEN THERE'S A ZONE OWE

GRAPH ON THE TOP WHEN YOU'RE

DOING ZONOGRAPHY OVER THE LIVER.

IF YOU LOOK OVER HISTOLOGY YOU

CAN ELIMINATE SOME OF THE

PROBLEM.

IT'S NOT A PROBLEM TO DIAGNOSE

IT UNDER A MICROSCOPE BUT WHEN

YOU VISUALIZE THOSE TUMOR CELLS

ARE JUST SORT OF INFILTRATING

THE NORMAL CELLS.

UNLESS THEY FORM A BIG MASS, HOW

ARE YOU GOING TO DETECT IT.

BE IT BY IMAGING OR CERTAINLY BY

PHYSICAL EXAM.

NOW THIS IS ONE OF THE BIG

PROBLEMS.

CIRRHOSIS OF THE LIVER, SCARRING

ON THE LIVER IS A MAJOR RISK

FACTOR REGARDLESS OF WHAT THE

EAT TAWLG FOETIOLOGY FOR THAT IS.

WE'LL GET INTO THAT IN A MINUTE.

THAT'S A SA SAW RATTIC LIVER AT THE

TOP.

IT LOOKS LIKE MULTIPLE HOLES IN

THE LIVER.

HIS YOHISTOLOGICALLY YOU CAN SEE THESE

ARE ROUND AREAS OF REGENERATION.

WHEN THE LIVER'S DAMAGED, IT

REGENERATES.

BUT IF THERE'S A LOT OF

SCARRING, IT ONLY REGENERATES IN

A RESTRICTIVE WAY SO IT PRODUCES

WHAT'S CALLED A NODULE.

THE BIG PROBLEM IS HOW DO YOU

TELL A NODULE FROM A TUMOR IN A

SAW RATTIC LIVER.

CIRRHOSIS IS A RISK LIVER.

PRIMARY LIVER CANCER IS A MAJOR

PROBLEM WORLDWIDE.

IT'S ESTIMATED THERE ARE OVER

700,000 NEW CASES DIAGNOSED EACH

YEAR AROUND THE WORLD.

IN THE INCIDENCE IT'S THE FIFTH

MOST COMMON CANCER IN THE WORLD

AND THE THIRD MOST COMMON CAUSE

OF CANCER-RELATED DEATHS.

AT LEAST THOSE ARE

APPROXIMATIONS BASED UPON

VARIOUS SURVEYS.

SO THIS IS A MAJOR PROBLEM.

SO LET ME TELL YOU BRIEFLY ABOUT

THREE INDIVIDUAL PATIENTS.

BECAUSE THESE ARE A BACKGROUND

TO THE DIFFERENT WAYS IN WHICH

THIS DISEASE PRESENTS ITSELF.

FIRST IS A VERY HEALTHY 23-YEAR

OLD MOZAMBIQUE GOLD AMERICAN.

HE WORKS A MILE AND-A-HALF DOWN

IN THE WORTH.

EATS MAYBE 5,000 CALORIES A DAY.

IS IN GREAT PHYSICAL CONDITION.

AND WHEN HE NOTICES A LUMP IN

THE RIGHT SIDE OF HIS ABDOMEN,

THE DIAGNOSIS IS PRIMARY LIVER

CANCER AND HE'S DEAD WITHIN A

YEAR.

THE SECOND IS A 55 YEAR OLD

AMERICAN FEMALE WHOSE HAD

CHRONIC HEPATITIS AND CIRRHOSIS,

FIBROSIS FOR MAYBE 20 YEARS.

AND A MASS IN THE LIVER IS

DISCOVERED BECAUSE PEOPLE ARE

DOING SERIAL ULTRA COUNTED

LOOKING FOR SOMETHING --

ULTRASOUND LOOKING FOR SOMETHING

LIKE THAT MASS AND IT APPEARS

IT'S PRIMARY CANCER.

THAT'S PROBABLY THE MAJOR FORMAT

IN WHICH WE SEE IT IN THIS

COUNTRY.

BUT THE THIRD IS ALSO VERY

COMMON.

A 70 YEAR OLD CHINESE GENTLEMAN

COMES TO AMERICA 15 YEARS AGO.

HAS A CHECK UP, HAS A LIVER

MASS, PRIMARY LIVER CANCER.

NOW WHAT THESE PEOPLE ALL HAVE

IN COMMON IS THAT THEY ARE

CARRIES OF HEPATITIS B VIRUS

AND/OR HEPATITIS C VIRUS.

LET'S TALK A MINUTE ABOUT HOW A

CLINICIAN DIAGNOSIS THIS

DISEASE.

I TOLD YOU THAT MOST PRIMARY

LIVER CANCERS ARE NOT

SYMPTOMATIC AND THE REASON IS,

AS YOU COULD SEE FROM THE

HISTOLOGY, AND ALSO BECAUSE THE

LIVER DOESN'T HAVE SENSORY NERVE

ENDINGS.

THE ONLY TIME YOU GET PAIN FROM

THE LIVER IS WHEN SOMETHING

EITHER STRETCHES THE CAPSULE

WHICH IS A LYNN LAYER OF CELLS

THAT -- THING LAYER OF CELLS

THAT SURROUNDS IT OR IF A TUMOR

HAPPENS TO INVADE IT, THEN YOU

GET ACUTE PAIN.

BUT OTHERWISE THERE MAY BE A

DULL ACHE IF THERE'S A BIG

TUMOR.

SO IT'S NOT AT THE TREATABLE

STAGE WITH MUCH SYMPTOMS.

THE SYMPTOMS ARE DUE TO THE

BEHAVIOR OF THE TUMOR.

OF THESE TUMORS HAVE A UNIQUE

PROPERTY WHICH WE DON'T FULLY

UNDERSTAND FOR INVADING BLOOD

VESSELS.

PRIMARY LIVER CANCER CAN

ACTUALLY CLIMB UP THE HEPATIC

VEIN.

THAT'S THE WAY BLOOD GETS FROM

THE LIVER BACK TO THE HEART, CAN

ACTUALLY CLIMB UP INTO THAT

VESSEL AND THROMBOSE THE WHOLE

THING.

LEADING TO A MAJOR MAYBE HAPPEN

QUICKLY OR SLOWLY BUT A MAJOR

CONSEQUENCE.

THEN YOU CAN DIAGNOSE IT.

OR IT INVADES THE PORTAL VEIN

WHICH DELIVERS BLOOD FROM THE

INTESTINE TO THE LIVER

PROCESSING WHAT'S CALLED PORTAL

HYPERTENSION.

PEOPLE CAN BLEED FROM THAT.

OR SOMETIMES IT ACTUALLY INVADES

BIO DUCTS AND PRODUCES BIL BILL

REA -- IT HAS TO DO SOMETHING

BEFORE IT BECOMES OBVIOUS FOR

THE MOST PART.

AND ALTHOUGH PEOPLE CAN COMPLAIN

OF WEAKNESS IS TIREDNESS AND

LOSS OF APPETITE, THERE ARE MANY

THING THAT CAN CAUSE THAT SO

IT'S NOT SO SPECIFIC.

SO IT'S NOT A SURPRISE THAT IN

EARLY DIAGNOSIS IN A BERN WHO

DOESN'T HAVE A MAJOR RISK FACTOR

IS NOT A COMMON EVENT.

SOMETIMES THESE TUMORS DO

REALLY STRANGE THINGS THEY

REARRANGE THEIR DNA AND STARTS

MAKING HORMONES.

ONE OF THE HORMONES IT CAN MATE

IS EPO -- MAKE IS EPO.

THAT STIMULATES RED CELL

PRODUCTION.

SO YOU CAN HAVE VERY HIGH

HEMOGLOBIN LEVELS.

THEY MAKE SOMETHING CALLED

PARATHYROID HORMONE AND THAT

FROZE THE CALCIUM LEVELS.

THESE ARE VERY RARE PHENOMENA

BUT IT SHOWS THE POTENTIAL OF

IT.

SO THIS IS THE WORLDWIDE

INCIDENCE OF THIS DISEASE, THE

BLACK ONES ARE THE MORE SEVERE.

SO YOU SEE IT'S A DISEASE OF THE

ORIENT.

A DISEASE FOR THE SUB-SAHARAN

AFRICA AND ANOTHER CENTERS

AROUND THE WORLD.

BUT IT'S A WORLD-WIDE DISEASE.

AND IT SORT OF MATCHES UP, THIS

IS AN OLD SLIDE OF THE

PREVALENCE OF A MARKER FOR

HEPATITIS B VIRUS, 1997.

THERE'S SIMILAR AND THE

HEPATITIS C PARALLELS IT BUT

MAYBE -- WILL COMMENT ON THE

ACCURACY OF THEM THIS IS THE

SUPER IMPOSITION OF THE CANCER

AND THE HEPATITIS B THAT WAS ONE

OF THE FACTORS THAT LED THE

DISCOVERERS OF THE HEPATITIS B

TO THINK THAT THIS MAY ACTUALLY

HAVE SOMETHING TO DO WITH THE

CANCER.

AND SO HERE ARE THE ESTIMATED US

CANCER DEATHS.

THE IMPORTANT THING IS THIS IS A

DISEASE THAT IS MORE COMMON IN

MEN THAN WOMEN.

WE DON'T FULLY UNDERSTAND WHY,

IT MAY HAVE TO DO WITH THE VIRUS

ETIOLOGY AND THE REACTION OF THE

DIFFERENT GENDERS TO VIRUSES.

BUT IT'S THE FIFTH MOST COMMON

CANCER DEATH CAUSE IN MALES AT

THE 7TH OR 8TH IN FEMALES.

IT'S NOT AN UNCOMMON DISEASE.

AND DUE TO THE IMMIGRATION IN

THE UNITED STATES, PARTICULARLY

FROM THE ORIENT, DEATHS FROM

HEPATITIS -- FROM PRIMARY LIVER

CANCER ARE INCREASING IN THE

UNITED STATES.

AND SO THIS IS THE U.S.

INCIDENCE OF PRIMARY LIFERLT

CANCER OVER A PERIOD OF SEVEN

YEARS, AND I THINK THE MORE

RECENT DATA MERELY SHOW THAT

THIS TREND IS CONTINUING.

THE NUMBER OF DEATHS

PROGRESSIVELY INCREASES.

CORRESPONDINGLY, THE SAME

THING'S TRUE IN OTHER PARTS OF

THE WORLD.

AND HERE'S A SLIDE SHOWING THE

NUMBER OF DEATHS IN JAPAN IN THE

PAST 44 YEARS.

AND YOU WILL NOTICE THAT AFTER

ABOUT 1976-1979, THE FREQUENCY

OF DEATHS FROM THIS DISEASE

INCREASES SUBSTANTIALLY.

YOU'LL ALSO NOTICE SOMETHING

ELSE, THAT THIS IS PREDOMINANTLY

A DISEASE OF OLDER INDIVIDUALS.

THIS IS NOT A DISEASE OF

CHILDHOOD OR VERY YOUNG ADULTS.

THE FREQUENTLY REALLY GOES UP

WHEN YOU GET TO BE IN YOUR, OH,

LATE 50'S AND UPWARD.

NOW, IT'S ONE OF THE FEW CANCERS

WHERE THERE ARE WELL-DEFINED

MAJOR RISK FACTORS AND ALL KINDS

OF EPIDEMIOLOGICAL AND OTHER

STUDIES, EXEXPERIMENTAL STUDIES

CONFIRM THIS.

THE MAJOR RISK FACTORS ARE THE

HEPATITIS B AND HEPATITIS C.

THERE'S GOOD EVIDENCE THAT

ALCOHOL IS A RISK FACTOR.

NOT THE OCCASIONAL FORT FRIDAY NIGHT

WINE KIND OF ALCOHOL BUT SAW

ROSE AND OTHER FORMS --

CIRRHOSIS AND OTHER FORMS OF

LIVER DISEASE.

TALK ENGINES PLAY A PART

ESPECIALLY SOUTH AFRICA WAS

THOUGHT TO BE ASSOCIATED WITH

THE ACCELERATED RATE OF

TUMORRED -- LIKE FOR EXAMPLE IN

THE MOZAMBIQUE GOLD MINE.

NOW THIS WAS A YOUNG MAN THESE

PEOPLE GOT HEPATITIS B FROM

THEIR MOTHERS ALTHOUGH THEY'VE

HAD IT FROM 20 YEARS BUT THEY

DIDN'T HAVE CIRRHOSIS OR

ANYTHING LIKE THAT.

SO ALWAYS FEELING THAT SOMETHING

ELSE WAS GOING ON AND THERE WAS

A LOT OF OF LOW TOXIN AROUND.

IT'S SHOWN THAT AFLOTOXIN HAS A

SPECIFIC TARGET ON P53, ONE OF

THE FACTORS THAT CAN BE MUTATED

IN THIS DISEASE.

NOW THE OTHER IS A METABOLIC

DISEASE, IRON STORAGE DEAL.

HEMO CHROME TOASTS WHERE IRON

AND EXCESS EXERTS A SPHREE

RADICAL EFFECT WHICH ACTS AS A

TUMOR GENIC.

YOU'LL NOTICE A COUPLE OF

INTERESTING THINGS BOTH AS

GEOGRAPHIC DISTRIBUTION IN

WHAT'S THOUGHT TO BE THE

ETIOLOGIC FACTOR, MOST NOTABLY

IN ASIA AND AFRICA, HEPATITIS B

VIE RUSSIAN, DESPITE THE

AVAILABILITY OF AN EFFECTIVE

VACCINE WHICH HAS BEEN AVAILABLE

FOR 20 OR MORE YEARS NOW,

HEPATITIS B VIRUS IS THE MAJOR

CAUSE OF PRIMARY LIVER CANCER IN

AFRICA.

THERE'S BEEN A SHIFTER IN THE

REST OF THE -- SHIFT IN THE REST

OF THE WORLD MORE TOWARD

HEPATITIS C BEING THE

PREDOMINANT.

NOW HERE'S AN INTERESTING THING

TO KEEP IN MIND.

WHAT IS A RISK FACTOR?

EVERYONE IS CONCERNED ABOUT

BEING IN A RESTAURANT WHERE

THERE'S SECONDARY SMOKE.

YOU SHOULD KEEP IN MIND THAT THE

SURGEON GENERAL REPORTED THAT A

MAC A DAY SMOKERS HAVE A 20-FOLD

RELATIVE INCREASE IN DEVELOPING

PRIMARY LUNG KARNLINGS WHEN

COMPARED TO NON--- CANCER WHEN

COMPARED TO NON-SMOKERS WHERE

CHRONIC HEPATITIS B CARRIERS

HAVE A HUNDRED FOLD RELATIVE

RISK OF DEVELOPING PRIMARY

CANCER.

SO THIS IS A MAJOR RISK FACTOR.

IT'S SO MAJOR THAT PEOPLE THINK

OF IT EAT LOGICALLY, NOT -- EAT

LOGICALLY, NOT IN SOME

ASSOCIATED KIND OF WAY.

SO THIS IS A SLIDE SHOWING THAT

THE ETIOLOGY CHANGED -- WELL IT

CHANGED BECAUSE THIS IS IN JAPAN

PRIOR TO 1988 OR SO THERE WAS NO

WAY OF DETECTING HEPATITIS C.

SO MOST OF THIS BARRED PRIOR TO

THEN OR YELLOW BECAUSE THEY WERE

UNKNOWN.

BUT THE MAJORITY OF THOSE WHICH

WERE UNKNOWN TURNED OUT TO BE

HEPATITIS C.

WHICH YOU'LL ALSO NOTICE THAT

THE FREQUENCY OF HEPATITIS B AS

SHOWN IN THE GRAY-LIKE BARS

DECREASES AND I THINK THAT'S

PRIMARY ASSOCIATED WITH THE

INTRODUCTION OF VACCINE AND

PREVENTION OF THE MATERNAL CHILD

SEQUENCE, THE PERINATAL

INFECTION.

IN THE UNITED STATES, I DON'T

KNOW WHAT THE CURRENT

INFORMATION IS AS TO THE

DISTRIBUTION.

MY GUESS IS HEPATITIS C IS

PREDOMINANTLY FOUND IN PATIENTS

WITH PRIMARY LIVER CANCER.

I MEAN HERE IN 2003 IT'S, 47%.

I DON'T KNOW WHAT IT IS NOW.

OKAY.

BUT THE POINT HERE IS IF YOU

TAKE A LARGE GROUP OF PEOPLE IN

THE UNITED STATES WITH PRIMARY

LIVER CANCER AND YOU LOOK, THE

VAST MAJORITY OF THEM HAVE

HEPATITIS C OR HEPATITIS B.

AND SOME OF THEM HAVE BOTH.

NOW THE OTHER THING THAT'S

EMERGED, DIABETES.

AND SOMEWHAT LESS CLEAR, OBESITY

IS A RISK FACTOR.

SO THIS WAS A STUDY FROM A LARGE

GROUP OF DIABETIC PATIENTS AND

IT WAS FELT THAT JUST DIABETES

ALONE CONFERRED LIKE TWICE

TWO-FOLD INCREASE.

YOU MIGHT ASK IF SOMEBODY HAS

CIRRHOSIS, WHAT'S THE RISK OF

THEM DEVELOPING PRIMARY LIVER

CANCER.

SO HERE IS SOME DATA THAT GIVE A

CLUE THAT WITH VIRAL INFECTION,

IF YOU HAVE CIRRHOSIS, THE

CHANCES ARE SEVERAL FOLD GREATER

OF DEVELOPING PRIMARY LIVER

CANCER THAN IF YOU DON'T.

BUT IT ALSO SAYS THAT YOU DON'T

HAVE TO HAVE CIRRHOSIS IN ORDER

TO DEVELOP PRIMARY LIVER CANCER

ASSOCIATED WITH EITHER OF THESE

TWO MAJOR VIRUSES.

IF YOU HAVE BOTH OF THEM

UNFORTUNATE ENOUGH TO BE A CARRY

OF BOTH THEN THE RISK FACTORS GO

UP SUBSTANTIALLY WHETHER YOU

HAVE CIRRHOSIS OR NOT.

NOW THIS IS AN INTERESTING

CUMULATIVE INCIDENCE OF CANCER.

IN CIRRHOTIC PATIENTS, AND

THERE'S ONE THING THAT'S SORT OF

INTERESTING AS SHOWN HERE ON

YOUR LEFT, THE TOP ONE.

YOU SORT OF WONDER WHY PEOPLE

WITH HEPATITIS C IN JAPAN SEEM

TO HAVE A MUCH HIGHER RISK OF

PRIMARY LIVER CANCER THAT THEY

DID IN THE OTHER PARTS OF THE

WORLD.

AND YET THEY ARE ALL CARRIERS OR

INFECTED WITH HEPATITIS C.

AND I DON'T KNOW THAT THERE'S AN

ANSWER TO THAT BUT WE'LL SEE.

ON THE OTHER SIDE IS JUST

SHOWING RISK FACTORS WITH OTHER

FORMS OF CIRRHOSIS, HEMATOMA

CHROME TOASTS, THE RISK IS LESS,

ALCOHOL IS LESS AND PRIMARY

BILLIARY CIRRHOSIS IS PROBABLY

JUST SLIGHTLY ABOVE WHAT THE

NORMAL POPULATION WOULD BE.

IF YOU ADJUST FOR AGE THERE

SEEMS TO BE SOMETHING THAT RACE

HAS TO DO WITH IT.

I DON'T KNOW WHETHER RACE IS THE

RIGHT WORD HERE BUT WHAT THEY'RE

TALKING ABOUT ARE WHITE, BLACK

AND OTHER AND THE OTHER IS

PRIMARILY CAUCASIANS --

ORIENTALS WHO HAVE A MUCH HIGHER

INCIDENCE.

RATE.

IT'S CONSISTENTLY AFRO AMERICANS

AT A MUCH SIGNIFICANTLY HIGHER

INCIDENCE RATE THAN CAUCASIANS.

AND I DON'T THINK WE HAVE A CLUE

AS TO WHY THAT HAPPENS.

LET'S TALK A LITTLE BIT ABOUT

WHAT CAN BE DONE FOR THIS

DISEASE.

THE BIG THING THAT CAN BE DONE

IS TO PREVENT IT.

YOU CAN'T PREVENT THE WHOLE

THING BUT THE HEPATITIS B

VACCINE, ACCORDING TO THIS

AUTHORITY, WAS DESIGNED TO

PREVENT A MAJOR HUMAN CANCER.

I DON'T KNOW IF IT WAS DESIGNED

TO DO THAT.

IT TURNED OUT TO DO THAT AND IT

WAS HOPED IT WOULD DO IT.

AND HE REMAINS THE ONLY SUCH

VACCINE IN WIDE USE, WIDE USE.

THERE'S A PAT LOAM AWE VIRUS

VACCINE BUT THAT'S NOT IN WIDE

USE.

THAT PREVENTS.

>POLY OWE MAINFECTION OF THE UTERUS AND SO

FORTH.

WHAT HAPPENS IN THE COMMUNITY

WHEN YOU HAVE A HIGH FREQUENCY

OF HELP TIE PISS B AND YOU

VASCULAR -- HEPATITIS B AND YOU

VACCINATE PEOPLE AND YOU SEE

WHAT HAPPENS OVER THE TIME WITH

CANCER.

SUCH A COMMUNITY WAS ON THE

ISLAND OF TAIWAN WHERE THE

FREQUENCY OF HEPATITIS B

INFECTION WAS EXTREMELY HIGH.

AND IN 1984, THEY STARTED A

NATION-WIDE EVERYBODY GOT

VACCINATED.

AND THEN HOVER  OVER A PERIOD OF TIME

THEY FOLLOW THE ANNUAL INCIDENCE

AND IT PROGRESSIVELY DECREASE.

NOW THESE DATA ENDED IN 1994.

I HAVE BEEN TOLD, THAT THE

INCIDENCE CONTINUES TO DECLINE.

BUT THE IMPORTANT THING IS THAT

VACCINATION AGAINST HEPATITIS B

WHICH WAS VERY COMMON IN TAIWAN

AND ALMOST UNIVERSAL IN PEOPLE

WITH PRIMARY LIVER CANCER, THEIR

VACCINATION AGAINST THAT VIRUS

PREVENTED IT.

PROBABLY THE MOST EFFECTIVE

ANTI-CANCER AGENT FOR SOLID

TUMORS THAT WE KNOW OF.

SO WHAT CAN BE DONE ABOUT IT.

WELL, SADLY NOT VERY MUCH.

AND THIS IS THE AREA OF

CHALLENGE AND I'LL END BY

POINTING OUT WHAT WE DO KNOW AND

WHERE THE CHALLENGING.

THE ONLY CURE IS SURGERY WHEN

THE POLYMER'S EXTREMELY SMALL.

THAT CAN EITHER BE BY RESECTION,

REMOVING PART OF A LIVER OR

TRANSPLANTING IT.

THOSE ARE THE ONLY CIRCUMSTANCES

WHERE ANYBODY HAS EVER BEEN

CURED WITH THE DISEASE.

SO THE BIG PROBLEM IS HOW DO YOU

DETECT PRIMARY LIVER CANCER

EARLY.

PARTICULARLY IN INDIVIDUALS WHO

HAVE UNDERLYING CIRRHOTIC

DISEASE.

SO THAT'S KIND OF EASY.

YOU CAN'T SCREEN A WHOLE

POPULATION AT LEAST USING

SCANNING AND SONOGRAMS.

BUT IF YOU HAVE PATIENTS WHO

HAVE THESE CHRONIC VIRAL

INFECTIONS AND MAYBE CHRONIC

ALCOHOLICS AND CIRRHOSIS AND

ALL, A PHYSICIAN WOULD SCREEN

THEM AT SOME REGULAR INTERVAL.

EXACTLY WHAT THAT INTERVAL

SHOULD BE IS A LITTLE BIT

UNCLEAR AND HOW FAR YOU SHOULD

GO IN USING PARTICULARLY

EXPENSIVE TECHNOLOGY FOR

SCREENING IS ALSO NOT CLEAR.

THAT'S THE AREA.

THAT WOULD BE WONDERFUL IF THERE

WAS SOME SEROLOGICAL MARKER.

OR A GROUP OF MARKERS WHICH

COULD BE DONE FROM BLOOD TEST TO

PROVIDES A CLUE AS TO WHO SHOULD

THEN BE INVESTIGATED MORE FULLY.

AND THIS IS AN AREA OF

SUBSTANTIAL INVESTIGATION   BIT.

SO HAS  HERE'S A LIST OF THE MARKERS

THAT HAVE BEEN PROPOSED AT

DIFFERENT TIMES.

AND THIS IS BASED UPON

EXPERIMENTAL STUDIES AND VARIOUS

SOME MOLECULAR BIOLOGY STUDIES,

MICRO SATELLITE DNA MARKERS.

NOW MICRO RNA'S.

AT THE MOMENT A LOT OF THESE ARE

BEING EXPLORED AND PEOPLE ARE

TRYING TO FIGURE OUT WHETHER

THERE'S A COMBINATION OF THEM

THAT GIVES A CLUE.

WHAT DOES IT MEAN IF SOMEBODY

HAS ONE OF THESE MARKERS ALL BY

ITSELF.

THE SITUATION IS COMPLICATED

BECAUSE THE CHRONIC LIVER

DISEASE ON WHICH THE TUMOR IS

INGRAFTED OFTEN ALTERS THE

EXPRESSION OF THESE PROTEINS.

SO IT'S NOT A CLEAR CUT THING.

THIS IS AN AREA THAT REALLY IS A

UNION BETWEEN THE NEED OF MORE

BASIC SCIENCE TO INVESTIGATE

THIS MORE FULLY THAT BIOLOGY OF

THE TUMOR.

WE'RE GOING TO SKIP OVER THE TGF

ONE FOR NOW.

SO I TOLD YOU THE TREATMENT

FALLS INTO THESE TWO GROUPS, THE

CURATIVE AND I'LL SHOW YOU THE

RESULTS OF THAT.

AND THEN THERE ARE A WHOLE

SERIES OF WHAT YOU CALL SEMI

SURGICAL ATTEMPTS INJECTING

ALCOHOL INTO A TUMOR TO SHRINK

IT, TO REDUCE SYMPTOMS, SIDE

EFFECTS.

THERE'S RADIO FREQUENCY AWK

LATION AND MICROWAVE A LATION

AND EVEN CRYOAB LATION.

-- SO MANY ARE IN THE FORM OF

HIGH CONCENTRATION OF ANTI-TUMOR

DRUGS.

OTHERS ARE AGENTS THAT OCCLUDE

THE BLOOD VESSELS.

INCLUDING CHEMOTHERAPY.

NONE OF THESE ARE VERY

SUCCESSFUL ALTHOUGH THEY CAN

REDUCE THE SIZE OF TUMORS AND

PERHAPS INCREASE THE QUALITY OF

LIFE FOR A WHILE.

BUT THEY DON'T AFFECT LIFE SPAN,

THAT'S FOR SURE.

SO INITIALLY WHEN SMALL LESIONS

WERE FOUND, THEY WERE TREATED BY

REMOVING A PART OF THE LIVER.

NOT THE WHOLE LIVER.

AND THE ORIGINAL GUIDELINES WERE

THAT THE TUMOR HAD TO BE SMALL,

MAYBE NO MORE THAN THREE THAT

YOU COULD SEE.

THAT'S WHAT YOU CAN SEE.

BUT YOU SAW WHAT THE HI TAWLG

THAT THOSE -- HIS TAWL HISTOLOGY.

YOU MAY NOT BE AWARE BUT THE

SURGEONS ARE ABLE TO LIKE DERIVE

THE LIVER ASIDE FROM ITS LOBES,

THERE ARE LIKE SEGMENTS

DEPENDING ON THE BLOOD SUPPLY.

SO YOU CAN REMOVE A SEGMENT

WEIGHT THE PERSON BLEEDING TO

DEATH BECAUSE THE BLOOD SUPPLY

IS SPARSE AND THOSE ARE CLEAVAGE

AREAS.

THOSE ARE PRETTY HIGH TECHNOLOGY

SURGERY.

IT'S NOT JUST GET IN THERE AND

CUT IT OUT.

NOW IF YOU REMOVE THE SURGICAL

RESECTION, REMOVE ONE LOBE OF

THE RECEIVE LIVER WHERE THE TUMOR IS HUH

LOOK OVER HERE AT THE FIVE YEAR

SURVIVALS.

THEY LOOK PRETTY GOOD BUT THESE

ARE EARLY CANCERS.

THE LIFE SPAN WHEN CANCERS ARE

DETECTED THEY ARE NOT ALL AS

LETHAL AS THE CASE I MENTIONED

TO YOU WITH THE GOLD MINER.

SO PATIENTS LIF LIVE FOR THREE,

FOUR, TIMES FIVE YEARS.

THEY REALLY KNOW WHAT THE

CONTROL GROUP IS FOR THIS.

NOW THE IMPORTANT THING THOUGH

IS ABOUT 70% OF THESE PEOPLE

HAVE A RECURRENCE AFTER PARTIAL

RESECTION.

AND THIS SLIDE SHOWS IT.

IT WAS THIS FINDING THAT LED TO

THE REALIZATION THAT MAYBE SMALL

TUMORS SHOULD BE TREATED LIKE

TRANSPLANTING THE WHOLE LIFER

BECAUSE YOU REALLY DON'T --

WHOLE LIVER BECAUSE YOU REALLY

DON'T KNOW WHERE THESE LITTLE

ISLANDS OF TUMORS ARE THAT YOU

CAN'T DETECT BY ANY OTHER MEANS.

AND THEN AFTER RESECTION,

VARIOUS THINGS WERE GIVEN IN AN

ATTEMPT TO PREVENT RECURRENCE.

NONE OF THEM REALLY HAVE WORKED

OUT.

SO THEN CAME LIVER

TRANSPLANTATION, TRANSPLANT THE

WHOLE ORGAN.

AND THESE ARE SOME OF THE

CONTRAINDICATIONS THAT SURGEONS

USE BEFORE DOING IT.

THEY ARE PRETTY SELF

EXPLANATORY.

THE PSYCHOSOCIAL SUPPORT THING

IS SOMETHING I DON'T WANT TO

COMMENT ABOUT BECAUSE HAVING A

LIVER TRANSPLANT IS NOT, YOU

HAVE IT, YOU'RE BETTER,

EVERYTHING'S THE SAME.

ON THE CONTRARY, LIFE IS NOT THE

SAME AND IT REQUIRES A WHOLE

SUPPORT MECHANISM DRUGS THAT

INHIBIT THE IMMUNE RESPONSE.

BUT LIFE IS MUCH BETTER THAN

HAVING A TUMOR, OF COURSE.

AND SO HERE ARE RESULTS OF

ACTUARIAL SURVIVALS, FIVE YEARS

IN THESE PATIENTS.

THE LIVER, THESE ARE CURED.

THESE ARE NOT RECURRENTS.

I MEAN, WHERE ARE THEY GOING TO

RECUR FROM.

THE ONLY THING THAT COULD HAPPEN

IS MAYBE THERE WAS A METASTASIS

THAT WAS RECOGNIZED BUT THESE

BASICALLY ARE CURES.

NOW THE PROBLEM OF COURSE IS

THAT THE SCAN HAPPENED OVER

NIGHT.

THERE'S A HUGE WAITING TIME.

YOU MAY BE AWARE THAT PEOPLE

TALK ABOUT THE SUPPLY OF THE

LIVER MAY BE I GUESS GLOBALLY IS

5,000 OR IS THAT THE UNITED

STATES?

I'M NOT SURE.

BUT THE POINT IS THERE ARE AT

LEAST THREE TIMES AS MANY PEOPLE

WHO WERE ON THE WAITING LIST FOR

THIS.

AND SO IT TAKES A LONG TIME

BEFORE YOUR NUMBER COMES UP AND

YOU CAN HAVE A LIVER.

THERE ARE OTHER REQUIREMENTS

THAT ARE NEEDED.

SO THIS IS THE AREA WHERE PEOPLE

DONATE PART OF THEIR LIVER.

THE LIVING DONOR, PARTICULARLY I

SUPPOSE IF YOU'RE AN IDENTICAL

TWIN, THAT'S A PERFECT

SITUATION.

BUT YOU CAN REMOVE HALF OF A

PERSON'S LIVER AND IF YOU'RE

WOOZY FOR A WHILE BUT THE LIVER

REGENERATES WITHIN A PERIOD OF

SEVERAL WEEKS OR SO.

AND THIS IS A VERY EFFECTIVE

THING BECAUSE IT'S NOT DONE IN

SOME EMERGENCY.

IF SOMEBODY TYPES ON A HIGHWAY,

ON AN ACCIDENT THAT HAS AGREED

TO HAVE THEIR LIFER USED FOR

TRANSPLANT -- LIVER USED FOR

TRANSPLANT, IT HAS TO BE

HARVESTED, IT HAS TO BE KEPT

ALIVE WHICH CAN ONLY BE DONE FOR

A PERIOD OF MAYBE EIGHT OR NINE

HOURS.

AND THE PATIENT HAS TO BE

BROUGHT IN AND EVERYTHING IS,

YOU KNOW.

AND THAT'S QUITE DIFFERENT FROM

A LIVING DONOR WHERE YOU WALK

INTO THE HOSPITAL AND HAVE AN

APPOINTMENT AND CROSS YOUR

FINGERS.

THESE ARE THE RESULTS OF THESE

DIFFERENT A BLATEIVE THERAPIES

WHICH CONTROL THINGS TO SOME

EXTENT BUT NOT VERY MUCH.

IT HAS BEEN UNREWARDING FOR

THESE DISEASES FOR REASONS

YOU'LL HEAR ABOUT.

THEN THERE ARE A WHOLE SERIES OF

SYSTEMIC THERAPIES.

THE ONE RIGHT AT THE TOP --

WHICH YOU'LL HEAR MORE ABOUT

FROM JEAN PIERRE.

THIS IS A UNIQUE DRUG WHICH WAS

THE ONLY DRUG THAT WAS LICENSED

BY THE FDA TO TREAT PRIMARY

CANCER OF THE LIVER.

IT WAS DEVELOPED TO THE

TREATMENT OF RENAL CELL

CARCINOMA.

WHAT MAKES IT UNIQUE IS THAT THE

PROPERTIES OF THE DRUG ARE THAT

IT INHIBITS A VARIETY OF

TYROSINE AND SOME SYRIAN

KINASES.

IT'S THE MAC KINASE PATH WAY.

SO THAT'S WHAT WILL HOPEFULLY BE

A SERIES OF DRUGS THAT ARE

TARGETED TO INHIBIT ONE OR MORE

OF THE MANY PATHWAYS WHICH ARE

DISTURBED IN THIS DISEASE.

IN THE ONE PUBLISHED CLINICAL

TRIAL IN THE NEW ENGLAND JOURNAL

OF MEDICINE, SURVIVAL WAS

INCREASED BY A MATTER OF ABOUT

THREE TO FOUR MONTHS.

BUT THE QUALITY OF LIFE HAS NOT

CHANGED.

AND IT'S A STEP IN HOPEFULLY A

RIGHT DIRECTION.

NOW THIS IS THE SAD FACT.

THAT ALMOST NO MATTER WHAT'S

DONE, THE SURVIVAL WITH PRIMARY

LIVER CANCER IS NOT GOOD.

AND YOU CAN SEE HERE BY FOUR

YEARS THE VAST MAJORITY OF

PATIENTS HAVE DIED.

AND THIS IS IRRESPECTIVE OF

WHETHER THEY HAVE UNDERLYING

CIRRHOSIS WHICH COMPLICATES THE

SITUATION OR NOT.

SO THIS IS REALLY A BAD DISEASE.

IT'S PREVENTIBLE.

SO WHAT HAVE I SAID FROM THE

CLINICAL PERSPECTIVE.

THAT THE CHANGING GEOGRAPHIC

DISTRIBUTION IS LARGELY DUE TO

THE CHANGING DISTRIBUTION OF

HEPATITIS C.

THE MIGRATION FROM THE ORIENT TO

THE UNITED STATES, CASE THREE

FROM THE ONE THAT I GAVE YOU.

THE DIAGNOSIS IS DIFFICULT

BECAUSE CURABLE LESIONS ARE

ASYMPTOMATIC.

PROBABLY ABOUT HALF OF THE CASES

CAN BE PREVENTED BY VACCINATION

AGAINST HEPATITIS B VIRUS.

FOR THOSE WHO ARE HEPATITIS B

POSITIVE OR, YOU KNOW, WHO ARE

DESTINED TO BECOME I GUESS.

THE ONLY CURE IS LIVER

TRANSPLANTATION FOR SMALL

LESIONS.

NOW, THIS IS JUST THE CURRENT

STATUS OF CLINICAL FRUSTRATION.

WHAT GIVES GREAT HOPE IS THE

ENORMOUS INTEREST AND EXCELLENT

STUDIES IN TRYING TO UNDERSTAND

THE MOLECULAR BASIS OF

CARCINOGENESIS AND THE ROLE OF

THE VIRUS.

THERE WERE STUDIES SOME OF WHICH

HAVE BEEN PRESENTED HERE AT OUR

COURSE, PARTICULARLY BY --

FERGUSON, YOU CAN SEE IT IN THE

VIDEO ARCHIVE.

AS TO MECHANISMS OF

CARCINOGENESIS IN THIS DISEASE.

WHY ARE, WHY IS THIS TUMOR

INVARIABLY DRUG RESISTENT.

THAT'S ONE OF THE THINGS THAT

JEAN PIERRE IS GOING TO ADDRESS.

IT COULD VERY WELL BE THAT EVEN

THOUGH THE PATIENTS NEVER HAD AN

ANTICANCER DRUG, YOU HAVE TO

REMEMBER THAT MOST ANTI-CANCER

DRUGS ARE EITHER PRODUCTS OF

BACTERIA OR THEY ARE PLANTS OR

THEY ARE SOMETHING ELSE AND THE

FUNCTION OF THE LIVER OF COURSE

WAS TO TAKE ALL THAT STUFF,

SOME'S GOOD, SOME'S GARBAGE THAT

WE EAT AND IT COMES AND ABSORBED

THROUGH THE MORTAL SYSTEM AND IT

HAS TO GO THROUGH THE LIVER.

THE LIVER GETS A HEAVY DOSE OF

THESE POLY CYCLIC COMPOUND

PROBABLY EVERY DAY OF OUR OUR LIVES.

SO MAYBE THAT'S THE SOURCE OF

THE PRIOR DRUG ADMINISTRATION.

THAT IS CONJECTURAL.

ARE THESE KREAL CELLS GENOMICLY

IDENTICAL IN DIFFERENT PARTS OF

THE LIVER.

WHAT DIFFERENTIATES THOSE TUMORS

THAT DO WEIRD THINGS LIKE GROW

BLOOD VESSELS.

THEY ALL DON'T DO IT.

WHY DO SOME DON'T METASTASIZE

WIDELY TO OTHER ORGANS BUT

EXTENSIVELY WITHIN THE LIVER.

WHAT ACCOUNTS FOR THEIR UNUSUAL

PHENOTYPE AND DOES THAT

INFLUENCE THE PROGNOSIS.

SO UNDERSTANDABLY IN THIS DAY

AND AGE OF HIGH THROUGHPUT

ANALYSIS, WHETHER IT'S LOOKING

AT NOW MICRO RNAs OR MESSENGER

RNAs OR INDIVIDUAL PROTEINS,

GENE EXPRESSION.

ALL OF THESE TECHNIQUES

INCLUDING THE TAB LAWNICS IS

BEING BROUGHT TO BEAR ON THESE

DISEASE.

AND HOPEFULLY THAT WILL BE THE

AVENUE BY WHICH GOOD THINGS WILL

HAPPEN BUT OTHERWISE IS A VERY

DISMAL PROPOSITION.

SO TO DISCUSS THIS, WE'RE VERY

FORTUNATE TO HAVE JEAN PIERRE

GILLET WHO IS IN THE MICRO --

LABORATORY AT THE NATIONAL

CANCER INSTITUTE.

JEAN PIERRE GOT HIS PH.D. IN

BELGIUM AND HAS BEEN AT NIH FOR

FIVE YEARS NOW.

AND WAS RECENTLY GIVEN A FORMAL

APPOINTMENT.

AND HE HAS DONE SOME REALLY

ELEGANT WORK WHICH HE'S GOING TO

TELL US ABOUT AND DISCUSS THE

BROADER PICTURE OF THE

CONTRIBUTION OF HIGH THROUGHPUT

STUDIES TO THIS DISEASE.

IF THERE ARE ANY QUESTIONS,

PARTICULARLY COURT ONES, WE CAN

CONSIDER THEM -- SHORT ONES, WE

CAN CONSIDER THEM AT THIS TIME.

>> [INDISCERNIBLE]

>> YOU HAVE BEEN TO ENOUGH OF

THESE DISCUSSIONS WHERE THEY HAD

SESSIONS ON HEPATITIS C BY

EXPERTS FROM THE NIH TO KNOW

THAT IT'S A VERY COMPLICATED

VIRUS.

AND IT HAS SO FAR DEFIED VACCINE

DEVELOPMENT.

I REFER YOU TO LOOK AT THAT

MATERIAL WHICH IS ON THE LEFT.

>> JUST ONE COMMENT ABOUT WHY

JAPAN HAS HIGHER RATES OF

CARCINOMA THAN THE U.S.

IF YOU DIDN'T MARK YOUR -- YOU

CAN SHOW THAT THE VIRUS HAS BEEN

IN THE JAPANESE POPULATION

LONGER.

30 YEARS LONGER THEIR GENOTYPE

IS INVENTED IN THE 9 1930'S AND

40'S WHILE WE WERE AT WAR AND WE

DIDN'T TARGET THE VIRUS UNTIL

1968 WITH THE DRUG EPIDEMIC.

SO OVER THE NEXT TWO DECADES OR

THREE HE CA DECADES WE'RE GOING TO

CATCH UP WITH JAPAN UNLESS WE

TREAT PEOPLE.

>> HOW DO YOU THINK THEY GOT IT

DURING THE WAR.

>> IT'S PRETTY CLEAR NOW THEY

GOT IT FROM NEEDLES.

THEY GOT IT FROM MASS

IMMUNEIZATIONS BUT MOSTLY THEY

GOT IT FROM SHOOTING UP FEMALES -- ANT

AT THAMAMPHETAMINES SHOOTING UP WITH

NEEDLES.

I'M SURE IT'S SPREAD AMONG THE

MILITARY WHICH WAS ALMOST THE

ENTIRE MALE POPULATION.

>> SO DO YOU THINK THAT THAT

CURVE THEN IS GOING TO BE

TRANSPOSED FROM THE ORIENT TO

NORTH AMERICA SUCH THAT OUR

POPULATION WILL REPLICATE THE

RISING.

>> IF YOU LOOK INTO JAPAN'S

CURVE, IT STARTS GOING UP.

IF YOU GO AGE-AGE DISTRIBUTION

CURVE, IT'S AROUND AGE 60 IS

WHEN IT STARTS TO TAKE OFF.

IN MOST OF THE CASES WHEN PEOPLE

WERE 70 AND 80 YEARS OLD AND

THEY GOT IT IN THEIR 20'S OR  

3078S.

IT'S THE -- 20'S OR   307S.

IT WAS IN INFECTION OR

DIMINISHING OF THE OLD AGE.

THE U.S. CURVE IS PEAKING AROUND

AGE 45 OR SO, 49.

SO WE'RE ABOUT 30 YEARS BEHIND

THEM.

AND ALL WILL CATCH UP, AND WE

ARE CATCHING UP ALREADY, YOU'LL

SEE IT.

JIECIAL>> ANY OTHER QUESTIONS.

>> JOB.

> -- [INDISCERNIBLE]>> YES, THEY WERE ALL 
KAMAKAZI

PILOTS, ETCETERA.

>> THANK YOU.

GOING BACK TO A GRAPH THAT YOU

SHOWED EARLIER HOW THERE'S SHARP

INCREASE IN THE NUMBER OF CASES,

HOW MUCH IS IT A NUMBER OF

PEOPLE HAVE BEEN DIAGNOSED WITH

THIS TYPE OF CANCER AND HOW MUCH

IS IT THAT WE HAVE TECHNOLOGY

NOW THAT WE ARE ABLE TO DETECT

THOSE CANCERS AT THE EARLY STAGE

AS OPPOSED TO THE SAME RATE

EARLIER BUT NOW WE HAVE BETTER

TECHNOLOGY.

I DON'T KNOW IF YOU UNDERSTAND

MY QUESTION.

>> I'M SORRY I CAN'T QUITE

FOLLOW THE QUESTION.

>> [INDISCERNIBLE]

>> THE DIAGNOSTIC TESTS FOR

HEPATITIS C AND B ARE READILY

AVAILABLE.

THAT ASPECT OF IT IS NOT HIGH

TECHNOLOGY ANYMORE.

>> THE REASON WHY OR THE REASONS

WHY I ASK THESE QUESTIONS IS

BECAUSE YOU SAID DOES IT HAVE

DOMINANT SYMPTOMS, IT'S KIND OF

HARD TO DETECT WHEN YOU HAVE

THIS KIND OF CANCER SO I FIGURE

THAT MAYBE IT'S BEEN AROUND FOR

A LITTLE BIT AND THAT WE DON'T

KNOW THAT MUCH.

AND YOU ALSO MENTIONED THE FACT

THAT WE DON'T HAVE THAT MANY

MARKERS OR WE DO HAVE MARKERS

BUT THERE'S NUT ONE THAT'S

VERY -- NOT ONE THAT'S VERY

SPECIFIC FOR THIS TYPE OF

CANCER.

>> DO YOU WANT TO ANSWER THAT?

>> [INDISCERNIBLE]

TUMORS WILL JUST PROGRESS UNTIL

I THINK THE ACTUAL INCIDENCE

WILL BE THE SAME, IT'S JUST A

MATTER OF HOW SOON YOU FIND IT.

SO IT'S A REAL INCREASE IN A

NUMBER OF CASES AND THE NUMBER

OF CASES ARE INCREASING BECAUSE

PARTICULARLY WITH HEPATITIS C

BECAUSE HEPATITIS C BECAME

EPIDEMIC IN THE 1960'S AND 70'S

AND NOW THOSE PEOPLE ARE 40, 50

YEARS DOWN THE PIKE AND THEY'RE

STARTING TO GET THE CANCERS.

>> I THINK FOR THOSE OF YOU WHO

DON'T KNOW HARVEY IS A REAL

EXPERT IN HEPATITIS C, HAVING

BEEN ONE OF THE DISCOVERERCOVERERS OF

HELHEPATITIS B.

ANY OTHER QUESTIONS AT THIS

POINT?

OKAY, JEAN PIERRE.

>>

>> GOOD AFTERNOON EVERYONE.

I DIVIDED THIS PRESENTATION IN

TWO SHORTS THE FIRST PART IS THE

MECHANICKIC USE -- OF CANCER AND

THE SECOND PART IS THE NEW

STRATEGIC TO REVERSE --

RESISTANCE IN HEPATO --

CARCINOMA.

YOU WILL FILED OUT IT CAN BE

APPLIED TO ANY TYPE OF TUMORS.

THE MAIN GOAL OF OUR RESEARCH IN

THE LAB IS TO UNDERSTAND WHY

SOME CANCERS DO NOT -- RELAPSE

AFTER TREATMENT.

IN ORDER TO FIND WAYS TO REVERSE

THIS SO-CALLED DRUG RESISTANCE

AND THEREFORE IMPROVE THE

RESPONSE OF PATIENTS TO

TREATMENTS.

SO THE REASON -- CLASSES OF

DRUGS GIVE ME A DRUG, I WILL

GIVE YOU THE MECHANISMS FOR

RESISTANCE.

THE TRICKY PAR IS CELLS BECOME

RESISTENT TO -- MECHANICALLY

UNRELATED CLUGZ IN ADDITION TO

THE DRUGS INITIALLY

ADMINISTERED.

IT'S KNOWN AS DRUG RESISTANCE.

SO THERE ARE MULTIPLE MECHANISMS

AND I WON'T GO HERE INTO

DETAILS, I JUST WANT TO SIDE

SERCHLSEVERAL MECHANISMS THAT INCLUDES

DRUG INCREASE -- OR INCREASED

DRUG -- RESTORATION, INCREASE

EXPIRATION OF PHASE ONE AND

PHASE TWO METABOLISM.

INCREASE EXPRESSION OF DNA

REPAIR GENES.

APOPTOSIS DIVISION AND SO FORTH.

IT'S REALLY A NO PLUS TASK TO

OVERCOME DRUG RESISTANCE AND

IT'S WELL-KNOWN THAT -- WHICH IS

PROBABLY THE MOST STUDIED DRUG

TRANSPORTER IS CORRELATED WITH

AN ADVERSE OUTCOME IN --

LEUKEMIA.

NUMEROUS CLINICAL TRIALS HAVE

BEEN PERFORMED TO TRY TO

MODULATE THIS TRANSPORTER.

THE LAST ONE TRY -- AND MOST OF

THOSE TRIALS HAVE FAILED.

IT'S SOMETHING WE HAVE SEEN

COMMENTARY IN BLOOD THAT USES

THE EXPRESSION FROM THE NATIVE

AMERICAN THAT SAYS WHEN YOU

ARRIVE A DEAD HORSE IT'S WISER

TO DISMOUNT IT.

IN THAT COMMENTARY IT SUGGESTS

THAT WE SHOULD SOMEHOW GIVE UP

THOSE KIND OF -- AND PUT ALL THE

EFFORT AND RESOURCES TO OTHER

STRATEGIES.

SO YES IT SO DIFFICULT TO

TRANSLATE TO THE CLINIC WHAT WE

HAVE FOUND THOSE LAST 30 YEARS

IN THE LAB.

SO THE QUESTIONS WE'VE TRIED TO

ANSWER IN THE LAB IS THE REAL

RELEVANCE OF GENE EXPRESSION HAS

BEEN FALLING THROUGH CANCER

CELLS FOR -- TO DO THIS WE NEED

TO BEAR IN MIND VERY IMPORTANT

THING, IS THAT MOST OF THE GENES

BELONG TO HOMOLOGOUS GENE

FAMILIES.

SO THE VERY FIRST QUESTIONS THAT

WE NEED TO ANSWER TO IS WHAT'S

THE BEST ASSAY TO ASSESS THIS.

AND FEW YEARS AGO, WE HAVE THE

CURRENT GENE EXPRESSION FOR

FINDING ASSAYS AND I WANTED TO

EL ADMINISTRATE THE POINT HERE

WITH THE EXPRESSION OF ABCB1 IN

THE NCI60 PAM DETECTED BY THREE

TECHNIQUES.

WHOLE GENOME MACRO RAY AND

TWO -- PTR USING TWO DIFFERENT

CHEMISTRIES, SICKE CYBER GREEN AND --

WHAT YOU SEE HERE IS THE --

WHICH IS NOT REALLY A SURPRISE.

BUT WHEN YOU COMPARE BOTH REACT

PCR TECHNIQUE YOU SEE AND THE

TAKE HOME MESSAGE IS THAT

USING -- PCR, YOU CAN BE MUCH

MORE SENSITIVE AND SPECIFIC THAN

THE OTHER TECHNIQUES.

THE OTHER QUESTION WE TRIED TO

ANSWER IS THAT WELL OKAY, IF WE

START DOING THIS KIND OF THINGS,

STUDYING GENE EXPRESSION

PROFILE, CAN WE REALLY BELIEVE

THAT WE CAN FIND PROTEIN EXPRESS

AND CAN WE REALLY BELIEVE THAT

THIS PROTEIN IS FUNCTIONAL.

SO AGAIN WE USE THE NCI60

BECAUSE AS YOU KNOW -- DATA BASE

OF LI BIOLOGICAL FORMATION -- FOR

THE OLD TRANSPORTERS USING --

QRTPCR AND WE TRIED TO REFINE

WITH RESUPPOSITORY THAT WAS

PUBLISHED BY OUR -- REPOSITORY

THAT WAS PUBLISH BY OUR LAB A

YEW YEARS AGO TO SCREEN OUT

ANTI-CANCER DRUGS IN THE EARLY

STAGES OF DRUG DISCOVERY TO

SCREEN OUT POTENTIAL -- OF MAJOR

ABC TRANSPORTERS.

SO WE DID THAT, WE CORRELATED

THE IC50 VALUES WITH THE ABC

TRANSPORTER EXPRESSION.

HERE IS AN EXAMPLE -- IF YOU GET

THE STRONG CORRELATION WHEN

THESE -- BETWEEN THOSE TWO

VALUES THEN YOU HAVE -- AND

ACTUALLY WE WERE ABLE TO REFINE

THAT REPOSITORY.

AND THIS IS ONE EXAMPLE HERE.

SO FROM THE MESSENGER RNA

EXPRESSION LEVEL, WE WERE ABLE

ACTUALLY WHO FINE PROTON

SUBSTRATES OF THE TRANSPORTERS.

THIS IS AN EXAMPLE FOR -- A

WHICH IS SUBSTRATE OF ABC --

USING A PAIR OF -- ONE

EXPRESSING AN EMPTY VICTOR AND

ONE EXPRESSING THE TRANSPORTER

OF INTEREST.

HERE IS ANOTHER EXAMPLE FOR

ANOTHER TRANSPORTER.

SO AT LEAST FOR THE TRANSPORTER

WE CAN ASSUME THAT IF WE DID

THAT WITH THE MESSENGER RNA WE

BELIEVE WE WILL FIND THE PROTEIN

AND THAT THIS TRANSPORTER COULD

BE FUNCTIONAL.

SO WE COME BACK TO THE ORIGINAL

QUESTION.

WHAT'S THE CLINICAL -- SO WE

DECIDED TOOK WITH THE PACK MAC

CHEMISTRY AND WE WENT BACK TO

THE DRAWING BOARD -- OVER THE

PAST 30 YEARS AND WE LISTED ALL

THE GENES THAT SOME WERE RELATED

TO DRUG RESISTANCE AND WE NEED

TO REMEMBER TWO THINGS.

THE FIRST ONE MOST OF THOSE

GENES COME FROM STUDIES OF --

COUNTERCELLS.

THE SECOND THING IS THAT THOSE

GENES CAN MAYBE ADD RESISTANCE

EAT INTRINSICALLY OR ACQUIRED --

EITHER INTRINSICALLY OR

ACQUIRED.

AND THOSE GENES TO BE RESISTANCE

IN A PARTICULAR -- TYPES OF

CANCER.

SO AS AN INTEREST IN PROTEIN

RESISTANCE TO STUDY THIS KIND OF

RESISTANCE CHEMICALLY WITH

CHILDREN WHO HAVE CANCER.

SO WHAT WE DID IS THAT WE

STUDIED THE EXPRESSION OF 400

GREENS -- IN 80 PRIMARY

SERVICE -- CAS CARCINOMA IN BLUE AND

WE STUDIED THOSE GENES IN ABOUT

40 EFFICIENT SYMPTOMS ORIGINATED

FROM THE SAME CANCER.

I DO NOT SHOW IT HERE BECAUSE

IT'S BEYOND THE SCOPE OF THE

PRESENTATION THAT WE FOUND A

GENE SIGNATURE THAT PREDICTS

SURVIVAL OF THESE PATIENTS.

SO WHAT WE WANTED TO DO IS TO

IDENTIFY MODEL TO PLAY WITH

THESE GENES IN ORDER TO TRY

MODULATING THE RESISTANCE OF

THAT CANCER.

SO WHAT WE DID, WE SCREENED

VARIOUS OVARIAN CANCER CELL

LINES -- THOSE CANCER LINES WERE

EITHER IN 2D OR 3D USING

DIFFERENT SCAFFOLDS.

THERE WAS ALSO IN VIVO -- AND

THEN WE PERFORMED -- TRYING TO

SEE WHAT KIND OF MODEL WOULD

CLUSTER WITHIN THE CLINICAL

CIRCLES.

WE MADE THE STRIKING OBSERVATION

THAT NONE OF THE E VARIANCE

CANCER CELL LINES THAT WE TESTED

MATCHED ANY CLUSTER WITH ANY

CLINICAL SAMPLES.

SO AT THIS STAGE, I -- LET'S TRY

TO ADD THE INFORMATION GENERATED

FROM THE OTHER CANCER CELL LINES

OF THE NCI60 THAT BELONGS TO THE

CANCER TIN.

SO THEN WE SHOULD SEE A THIRD

GROUP ON THE LEFT OR RIGHT OR

WHATEVER, A THIRD GROUP WITH ALL

THESE CELL LINES THAT WOULD

CLUSTER   FROM THE OVERALL

CANCER AND APART FROM THE

CLINICAL CANCER.

AND THOSE ARE THE CELL LINES

REPRESENTED WITH MAGENTA.

AND STRIKINGLY WE FOUND THAT ALL

THE CELL LINES EITHER WERE IN

VITRO OR IN VIVO.

THERE'S MORE RESEMBLANCE TO THE

CENTERS THEY ARE SUPPOSED TO

MODEL.

INTERESTINGLY SO BEFORE I WOULD

LIKE TO SAY THAT WHEN YOU THINK

ABOUT THAT, THIS UPREGULATION

ACROSS ALL CANCER TYPE IS

CONSISTENT WITH THE IDEA THAT

EXPRESSION OF THE GENES THAT WE

ARE STUDYING ARE NECESSARY FOR

THE CELL LINES TO TRY IN THEIR

IN VITRO -- IN OTHER WORDS THE

ESTABLISHED CANCER CELL LINES

ARE ALREADY HIGHLY SELECTED FOR

THE EXPRESSION OF GENES

ASSOCIATED WITH DRUG RESISTANCE.

WE MADE THE SIMILAR OBSERVATION

FOR ALL THE TYPE OF -- INCLUDING

BLASTOMA, BREAST CANCER, MICRO

DISSECTED MELANOMA WITH THE

KNOWLEDGE THAT'S USING FEWER

CENTERS THAN THE PRESENT STUDY.

WE MADE A SIMILAR OBSERVATION

WITH LEUKEMIA SAYING THAT THIS

KIND OF OBSERVATION IS NOT

CONFINED TO SOLID TUMORS.

SO IN CONCLUSION, WE NEED BETTER

MODELS TO STUDY DRUG RESISTANCE

MECHANISM THAT MORE CLOSELY

MIMIC THE IN VIVO CANCER C -- SO

TO AVOID RADICAL CHANGES IN

PROFILES -- AND THIS IS AN

ONGOING RESEARCH IN THE LAB.

SO WE HAVE SEVERAL LEADS.

FIRST WE SUGGEST TO WORK WITH

PRIMARY TUMOR.

WE SHOULD GO WITH SHORT-TERM

CULTURE.

LOW OXYGEN TENSION EXAMINE WE

SHOULD WORK WITH A MORE

CONTROLLED MEDIUM.

THE MOST IMPORTANT OBSERVATION

THAT WE SHOULD CONSIDER IS THAT

TUMOR IN THE BODY ARE SLOW

GROWING AS OPPOSED TO THE

CULTURE OF CANCER CELLS IN THE

LAB THAT ARE GROWING QUICKLY.

AND THIS IS SOMETHING THAT IN

THE PRO PARAMETERS WE NEED TO STUDY

AND REFLECT.

SO IF IT'S REALLY THE SAME

OBSERVATION FOR THE LIVER

CANCER.

SO WHEN YOU LOOK AT THE

EXPRESSION PROFILE OF

HEPATOCYTES, WHAT OBSERVATION

YOU CAN MAKE IS THAT THE SIMILAR

GENE EXPRESSION PROFILES OF

NORMAL HEPATOCYTES AND NORMAL

RESIST ELSE IENCE IS STRIKING.

YOU CAN SEE HEPATOCYTES

OVEREXPRESSED THE GENES -- DRUG

RESISTANCE, THESE ARE DRUG

TRANSPORTERS, UPTAKE

TRANSPORTERS, NOT TO MENTION

CYTOKINE -- MANY HAVE USED THIS

ANALOGY TO DID JECKL DR. JECKLE AND MR.

HYDE.

IT'S A GREAT GUIDE FOR THE BODY

BUT WHEN A -- VASCULAR GENE

EXPRESSION PATTERN RENDERS IT TO

RESIST ANY KIND OF CHEMICAL

TREATMENT.

THERE IS POSITIVE RESEARCH ON

THE ENTRUSTABILITY OF HCC FROM

THE PERSPECTIVE OF -- DRUG

RESISTANCE.

THERE ARE A LOT OF STUDIES THAT

FOCUS ON PRODUCTIVE OF GENE

SIGNATURES OVER THE SURVIVAL OF

PATIENTS WITH HCCN.

AT THE NC IMPLET W CI WE HAVE WORLDWIDE

EXPORTS -- ATTENTION IS ALSO

BEING DIRECTED TOWARDS GENE

SIGNATURES ASSOCIATED WITH

PATHOGENIC PROCESS AS WE

INTRODUCE IT.

AND HERE WE HAVE REQUISITE

MECHANISMS IN CLINICAL SAMPLES

OF NORMAL LIVER AND -- CARCINOMA

WITH HBB.

SO WE WERE FORTUNATE TO

COLLABORATE WITH -- WHO GAVE US

ACCESS TO THE REPOSITORY.

AND WE HAVE CHOSEN TO

REINTERROGATE ABOUT 40 SAMPLES

OF LIFER CANCER.

CANCER -- LIVER CANCER.

THEY WERE CHARACTERIZED BY A

GROUP USING -- AND USING THE

EXPRESSION PROFILE THEY WERE

ABLE TO DISCRIMINATE THOSE

PATIENTS IN TWO GROUPS WHEREAS

ON THE SURVIVAL.

SO THE FIRST QUESTION WE ASKED

WAS WHILE WE HAVE 400 GENES, DO

THEY PROVIDE ENOUGH INFORMATION

TO DISCRIMINATE BETWEEN THOSE

THREE ENTITIES.

AND THEY DO.

FURTHER ANALYSIS WITH THE 45

GENE SIGNATURE THAT WE VALIDATED

USING AN INDEPENDENT COHORT OF

53 PATIENTS.

SO WE CAN PREDICT THE OVERALL

SURVIVAL OF THESE PATIENTS WITH

45 GENE SIGNATURE.

SO THERE ARE HUNDREDS OF PAPERS

THAT WE POST GENE SIGNATURES.

SO FROM THAT, WHAT DO YOU DO.

SO AS I SAID AT THE VERY

BEGINNING, ONE OF THE ULTIMATE

GOAL OF THIS WORK IS TO REVERSE

DRUG RESISTANCE AND FOR THAT WE

NEED TO PINPOINT NEW TREATMENTS.

AND WE HAVE AN INTERESTING PAPER

IN SCIENCE A FEW YEARS AGO ABOUT

THE CONNECTIVITY.

VERY BRIEFLY AS I CANNOT GET

INTO TOO MUCH DETAILS HERE, WHAT

THE CONNECTIVITY MAP PROVIDES

YOU IS GAM GENE EXPRESSION PROFILE

AND TWO PROVIDE AN ALGORITHM

THAT COMPARES THE DIRECTION OF

GENE EXPRESSION CHANGE BETWEEN

ONE TO ANOTHER IS THE CHANGE DO

TO DRUG TREATMENT.

SO IN OUR STUDY, WE WERE

INTERESTED IN FINDING DRUGS THAT

CAN POTENTIALLY INCREASE THE

SENSITIVITY OF GROUP PATIENTS

WHO ARE MEASURES WITH SURVIVOR

TO DIRECT TREATMENTS.

SO THE PURPOSE WAS WHEN WE, WHEN

COMPARED TO THE GROUP A

PATIENTS, THE GENE EXPRESSIONS

FOR THE PATIENTS OF SURVIVAL CAN

BE CONSIDERED TO BE INDICATIVE

OF DRUG SENSITIVITY.

SO USING THIS GENE EXPRESSION

PROFILE, WE INTERROGATED THIS

DATA BASE AND WE WERE GOING TO

FIND DRUGS GROW FLAVONE THAT

MIGHT REVERSE THE EXPRESSION

PROFILE FROM POOR RESPONDERS TO

GOOD RESPONDERS.

SO EVER WE COULDN'T FIND ANY

PEOPLE WHO WANTED TO PLAY THE

GUINEA PIGS.

SO WE WENT BACK TO THE BENCH AND

WE INTERROGATED ABOUT 20 TO 40

CELL LINES THAT WE FELT WERE

REFLT.

REFLT -- RELEVANT.

USING THE GENE SIGNATURE WE WERE

ABLE TO FIND CELL LINES ACTUALLY

AS OPPOSED TO THE OTHER CANCER

I'VE SHOWN CAN CLUSTER WITHIN

THE CLINICAL SAMPLES.

SO WE PICKED TWO CELL LINES THAT

WERE PLC AND -- THAT WE TREATED

WITH A DOSE O SUBLETHAL DOSE OF THE

COMPONENTS WE FOUND MANY WHEN WE

INTERROGATED THIS 45 GENE

SIGNATURE, WE WERE ACTUALLY, SO

WE WERE ABLE TO OBSERVE THAT

THESE WERE TREATMENT REVERSE THE

EXPRESSION PROFILE OF THE CELL

LINES FROM THAT OF POOR OVERALL

SURVIVAL TO THAT OF GOOD OVERALL

SURVIVAL.

SO NOW WE CAN REVERSE THE

EXPRESSION AND SO PATIENTS MIGHT

LIVE A LITTLE BIT LONGER.

BUT THAT'S THE TREATMENT, THAT'S

THIS REVERSAL, RESENSITIZED THE

TUMOR.

AND I SAY YES, IT DOES.

SO WHAT WE DID IS THAT WE FIRST

TREATED THE CELL LINE WITH THE

REVERSAL AGENTS, EITHER 60G

OR -- WE ALSO TREATED WITH

CONVENTIONAL CHEMOTHERAPY ALONE

SUCH AS -- FOR INSTANCE AND THEN

WE COMBINE THE TREATMENT.

SO WE PRETREATED FIRST FOR SIX

HOURS, REMOVED THE MEDIUM AND

THEN TREATED WITH THE

CONVENTIONAL AGENTS.

AND WE FIND THAT ACTUALLY THIS

PRETREATMENT SENSITIZED THOSE

CELLS TO PROMOTIONAL THERAPY.

THIS IS ANOTHER EXAMPLE TO SOME,

TEMPSOME -- TO SOME EXTENT IT WORKS

AND HERE WITH SOME RAFENIB.

WE TRIED TO IDENTIFY THE

MECHANISM OF FRACTION THAT

WORKS.

SO I PUT ASIDE THAT THESE DRUGS

COULD ACT AS HISTONE ACETYL ASE

INHIBITORS.

SO WE HAVE THE -- SO WHAT WE DID

IS THAT WE COMPARE THE UNTREATED

CELL LINE TO TREATED CELL LINES

WITH THE THREE AGENTS AND ALSO

WITH CONTROL WERE KNOWN IN THE

INHIBITORS WHICH ARE -- SO YOU

CAN SEE THAT ACTUALLY THE

TREATMENT INCREASES THE AWE

SETTLATION STATUS OF HISTONE NOT

AS DRAMATICALLY AS THE PEPTIDE

FOR INSTANCE BUT IT DOES.

THIS IS THE SAME RESULT, SAME

OBSERVATION WITH ANOTHER CELL

LINE AND WITH THE THIRD ONE.

SO YOU SEE AN INCREASE MODERATE

THAN AN INCREASE IN ARTICULATION

STATUS OF HISTONE H3.

SO IF THERE IS AN INCREASE IN

THE CIRCULATION, WE COULD THINK

THAT WE SHOULD AWK VERV OBSERVE AS WELL A

CHANGE IN THE MEDIATION STUDIES.

SO WE DID NOT DO ANY VERY

EXPENSIVE -- EXPERIMENTS TO

STUDY MANIPULATION STUDIES.

WHAT WE DID IS THAT WE FIRST

LOOKED AT THE REGION OF THE 45

GENE TO SEE HOW MUCH, HOW MANY

OF THEM SOMETIMES CPGI AND 32

OUT OF THE 45 GENE SIGNATURE.

SO WE USED THE OLD VERY

EFFICIENT METHOD THAT UPON TWO

ENZYME -- AND WE FOLLOWED THIS

UP WITH -- HERE IS AN

ADMINISTRATION WITH FIVE

CLINICAL SAMPLES.

WHAT WE DID IS WE HAD STUDY OF

12 GENES IN TUMOR CELLS AND IN

THE MUCH SURROUNDING LIVER.

AND WE COULDN'T SEE MUCH

DIFFERENCE IN THE METHYLATION

STATUS BETWEEN THE SURROUNDING

LIVER WHICH WE WOULD HAVE SAW

THAT IT WOULD BE UNMETHYLATED

WHILE THE TUMOR IS MET LATED.

THESE ARE THE TECHNIQUES FOR THE

STUDIES.

WHAT ABOUT THE CELL LINES THAT

WE USED.

SO THERE ARE THREE CELL LINES

THAT CLUSTERED WITH PATIENTS

WITH GOOD SURVIVAL AND MOSTLY

THEY ARE AT LEAST FOR THE 12

GENES AGAIN WE ARE UNMETHYLATED.

FOR PATIENTS WITH SURVIVAL STILL

WE OBSERVED UNMETHYLATION.

THERE ARE SOME GENES THAT ARE --

AND FOR THOSE GENES WHEN YOU

TREAT THE CELL LINE WITH EITHER

PEPTIDE THAT'S CONTROL 6TG, YOU

CAN SEE SLIDE DECREASE IN THE

METHYLATION STUDIES.

SO THE MAIN CONCLUSIONS OF THAT

WORK IS THAT WE IDENTIFY THREE

COMPONENTS THAT ADD THE ABILITY

TO COME FROM THE OTHER GENE

EXPRESSION PROFILE CELL LINES

FROM ONE MUCH IN MEASURES WITH

POOR OVERALL SURVIVAL TO ONE

WITH GOOD SURVIVAL CHARACTERS BY

INCREASING HISTONE AWE SETTLE

LATION RESULTING THE

SENSITIZATION OF TUMOR CELLS.

THIS IS GENE EXPRESSION

PROFILING AND CONNECTIVE THITY

DATA WHERE DISEASE WHERE NO

EFFECTIVE TREATMENT.

MORE IMPORTANTLY THE CURRENT

STUDY WITH THESE A NEW STRATEGIC

TO SENSITIZE ANY TYPE OF RETRACT

RETRACT -- REFRACTORY

CONFERENCE -- I WOULD LIKE TO

THANK -- WHO I HAVE BEEN WORKING

IN THE PAST SIX YEARS -- WITH

PROVIDING US CLINICAL SAMPLES

AND FROM BEING A GREAT

SUPPORT -- WHO HAS BEEN

EXTREMELY -- AND THANKS FOR YOUR

ATTENTION.

[APPLAUSE]

>> THANK YOU.

THANK YOU VERY MUCH.

THESE ARE SOME EXCITING

OBSERVATIONS, THE STUDY OF CELL

LINES [INDISCERNIBLE]

>> WOULD [INDISCERNIBLE] HOW

MANY OF THEM CARROTS T CORRESPONDS TO THE

[INDISCERNIBLE]

>> MOST OF THESE GENES I WOULD

SAY.

SO WE STUDIED TO BE 380 GENES.

POST OF THEM ARE EXPRESSED IN

THE NCI -- AND WE DID NOT ONLY

STUDY NCI60 PANEL BUT WE, TO

INTERGATE DRUG RESISTANCE, WE

USED ADDITIONAL OVARIAN CANCER

MODELS ISOLATED EITHER FROM

PATIENTS WHO UNDERWENT BEEN

TREATMENT AND ISOLATED SOME

PATIENTS WHO RELAPSE AFTER

TREATMENT WHO DID NOT ON THE

FIRST CHEMO.

SO IT'S NCI --

>> A SHORT QUESTION.

SO WHAT IN THE LIVER MAKES THEM

SO MULTIDRUG RESISTANT BECAUSE

PROBABLY THIS IS SAVING US FROM

THAT BECAUSE WE HAVE

[INDISCERNIBLE]

>> IT'S THE ORGAN, SO IT

EXPRESSES A LOT OF THE GENES

THAT WE LISTED FROM THE -- MAYBE

DRUG RESISTANT.

AND BASICALLY LIVER IS THERE TO

PROTECT US AGAINST -- SO THAT'S

HOW WE CAN EXPLAIN IT.

>> WE WERE JUST DISCUSSING

BEFORE THERE'S AN INTERESTING

PAPER IN THIS WEEK'S ISSUE OF

HEPITOLOGY SAY THAT THE MICRO

RNA THAT REGULAR LAY THESE ABC

TRANSPORTERS WHICH ARE UP

THEMSELVES UPREGULATED IN MANY

PRIMARY LIVER CANCER PATIENTS,

THE MY RO MICRO RNA'S ARE ACTUALLY

SUPRESSED.

AND SO THIS IS A STUDY WHICH

SUGGESTS THAT CIRCULATING MICRO

RNA'S MAY ACTUALLY BE EFFECTIVE

IN TURN SUPPRESSING THE OVER

EXPRESSION OF THE ABC

TRANSPORTS.

>> [INDISCERNIBLE]

>> I AGREE, YES.

ARE THERE ANY OTHER QUESTIONS OR

COMMENTS?

OKAY.

LISTEN JEAN PIERRE, THANK YOU

VERY MUCH.

THAT WAS VERY EXCITING WORK.