GOOD AFTERNOON. WE WILL GET STARTED. THERE ARE A FEW PEOPLE THAT HAVEN'T BEEN HERE BEFORE. I HAVE TO EXPLAIN WHY WE SHOW A PICTURE OF THE MOST FAMOUS BRIDGE IN THE WORLD. BECAUSE WE IN EFFECT ARE LIKE THOSE TWO GENTLEMEN ON THE BRIDGE BETWEEN NEW YORK AND BROOKLYN, AND THE WHOLE IDEA IS TO BRING TOGETHER SORT OF EXCIT ING ADVANCES IN KIND OF BASIC BIOLOGICAL AND ENGINEERING SCIENCES WITH MAJOR HUNDRED DISEASE PROBLEMS. AND TODAY'S TOPIC IS EXCELLENT EXAMPLE FOR THAT AS ARE OUR SPEAKERS. SO IT'S KIND OF SIGNIFICANT THAT JUST A COUPLE OF DAYS AGO, TOM, WHO WAS A DEAR FRIEND, AND REALLY CAN BE TRULY REFERRED TO AS THE FATHER OF MODERN TRANS PLANTATION. BACK IN THE 60S PEOPLE THAT HAD CHRONIC LIVER DISEASE OR CHILDREN WITH MANY INHERITABLE DISORDERS, THEY ALL DIED. IT WASN'T VERY MUCH THAT COULD BE DONE. THIS IS LONG BEFORE TREATMENT FOR VIRUS, HCV, VACCINE NATION. THESE WERE CHRONIC LIVER DISEASE IN YOUNG PEOPLE AND OLD PEEP. AND TOM HAD THE ABIDEING DESIRE TO REPLACE THE LIVER WHICH WAS NO MEAN TASK, BOTH FROM A TECHNICAL STANDPOINT, FROM ALL THE ORGANIZATION THAT'S REQUIRED IN ORDER TO CARRY OUT SUCH A PROCEDURE, AND THEN, OF COURSE, THE IMMUNOLOGICAL PROBLEMS THAT EMERGE. ALL OF WHICH CONTRIBUTED TO MOST OF THOSE EARLY PATIENTS IN THE 60S, THEY DIED. THE WHOLE SYSTEM WAS PUT OFTEN HOLD FOR ABOUT FIVE OR CYST YEAR S. SHORTLY THERE AFTER, I THINK TOM IS PROBABLY THE FIRST ONE WHO, THE IN LIVER FIELD, WHO CAME UP WITH THE NOTION OF USING IMMUNO SUPPRESSIVE DRUGS TO TRY TO REDUCE OR ELIMINATE GRAPH VERSES HOST REACTION. IT WASN'T UNTIL 506 CAME ALONG THIS REVOLUTIONIZED THE WHOLE PROCESS. LEVER TRANSPLANTATION BECAME AN ACCEPTED MODALITY. IT'S ACCEPTANCE WAS, TO A LARGE EXTENT, GREATRY INFLUENCED BY THE ENORMOUS ENERGY AND CONVICTION. TOM WAS A VERY CONVINCING PERSON IN LATER YEARS, HE CHALLENGED THE IDEA THAT ONE COUNTY DID NOT DEVELOP IMMUNE TOLERANCE. HE WENT SO FAR TO TAKE PATIENTS WHO HAD TRANSPLANTATION OFF IMMUNOSUPPRESSANT DRUGS. ABOUT A THIRD OF THEM ACTUALLY TOLERATED THAT. SO HE WAS INVOLVED WITH BASIC SCIENTISTS, PARTICULARLY [INDISCERNIBLE] AND OTHERS, IN THE STUDY OF IMMUNE TOLERANCE. SO HERE WAS AN EXTRAORDINARILY DYNAMIC ENERGETIC SURGICAL SCIENTIST AND TRULY THE FATHER, NOT THE LEAST OF HIS ACCOMPLISH MENTS WAS PROBABLY TRAINING, TWO GENERATIONS OF TRANSPLANT SURGEONS. AND I THINK HIS TRAINING PROGRAM INITIALLY IN COLORADO AND LATER IN PITTSBURGH CREATED THE MODEL THAT WE NOW HAVE WITH LIVER TRANSPLANTATION BE PERFORM FORM ED IN MOST MAJOR MEDICAL CENTERS AROUND THE WORLD. AND THE RESULTS ARE QUITE OUTSTANDING AS WE WILL HEAR TODAY. SO WE BLENDED TRANSPLANTATION WITH LIVER CARP CANCER FOR SEVERAL YEARS. A COUPLE NOTES OF THINGS YOU MIGHT THINK ABOUT IF YOU'RE NOT FAMILIAR WITH THIS. IT USED TO BE IF SOMEBODY HAD A PRIMARY LIVER CANCER, IN AN ACADEMIC CENTER IN NORTH AMERICA , THEY WOULD BE PRESENTED AT GROUND ROUNDS. IT WAS AN ODDITY, REALLY UNUSUAL IF YOU WERE IN SHANGHAI, CHINA, IF YOU HAD A MYOCARDIAL INFARCTION, YOU'D BE PRESENTED AT GRAND ROUNDS. THAT WAS PRETTY UNYOU BELIEVE. THE WORLD HAS CHANGED. NOW IT IS LESS FREQUENT ENASIA, BUT STILL IMPORTANTLY THERE, AND INCREASING IN NORTH AMERICA AND IN EUROPE. AND IN THE DISCUSSION THE WHYS BEHIND THIS. IT WAS DISCOVERED THAT THE DISTRIBUTION OF CANCER, WHICH WAS ALWAYS PUZZLING OF LIVER CANCER, FOLLOWED THAT OF HEPATITIS B VIRUS INFECTION. AND THIS IS PROBABLY THE ONLY CANCER THAT HAS EVER BEEN -- WELL, THERE IS ONE OTHER. THAT'S BEEN PREVENTED BY VACCINE NATION. AND THE EFFECT OF HBV VACCINE BOTH ON THE DISEASE AND PREVENTION AND ON LIVER CANCER IS REALLY ASTOUNDING. BUT THE DISTRIBUTION NOW FOLLOWS TO A GREAT EXTENT, THAT OF HEPATITIS C VIRUS, WHICH WE HAVE NO VACCINE. BUT WE HAVE CURATIVE DRUGS. AND THIS IS THE ONLY KNOWN VIRUS , I THINK, THAT CAN BE HOPE FULLY, LOOKS LIKE, CURED. BY PHARMACOLOGIC AGENTS, DIRECT ED AGAINST THE VIRUS. SO WHY IS IT INCREASING IN NORTH AMERICA? HOW DO YOU TELL IF YOU HAVE IT? NOT SO EASY. BECAUSE THE LIVER IS A HUGE ORGAN WITH LIMITED NEURO-INPUT. AND SO A TUMOR CAN SIT THERE AND YOU WOULDN'T EVEN KNOW IT WAS THERE. UNLESS YOU HAVE TO GO LOOK FOR IT OR YOU HAVE SOME MARKER TO IDENTIFY IT. AND AT THE MOMENT, THAT'S WHERE THE CONTROVERSIAL BATTLEGROUNDS. NOT BATTLEGROUNDS, BUT UNCERTAIN TIES. HOW DO YOU SCREEN FOR PEOPLE WITH PRIMARY LIVER CANCER? NOW, THE CANCER ITSELF IS DIFFERENT FROM MANY OTHERS. IT'S ALMOST ENDOGENOUSLY RESISTANT TO EVERY CHEAP THERAPEUTIC AGENT. HOW DO YOU TREAT IT? THE INITIAL IDEA OF TREATING LIVER CANCER BY TRAININGS TRANS PLAN NATION, WE KNEW LITTLE ABOUT HEPATITIS -- ABOUT PRIMARY LIVER CANCER AT THAT TIME. BUT IT TURNS OUT THAT FOR MANY PATIENTS, LIVER TRANSPLANTATION APPEARS TO BE A CURATIVE EFFECT. SO THIS IS THE BROAD AREA THAT WE'RE GOING TO HAVE DISCUSSED TODAY, AND WE WERE VERY FORTUNATE TO HAVE TWO OUTSTANDING INDIVIDUALS WHO MADE TRULY MAJOR CONTRIBUTIONS IN BOTH OF THESE FIELDS. THIS IS ALMOST MASSACHUSETTS GENERAL HOSPITAL DAY, BECAUSE BOTH OF THEM RECEIVED THEIR TRAINING AT THE MGH, BOTH GRADUATED FROM HARVARD MEDICAL SCHOOL. JAKE LIANG, I'M SURE KNOWN TO MOST OF YOU, HE'S CHIEF OF THE LIVER DISEASE BRANCH IN NIDDK, AND HE'S BEEN HERE SINCE 1996. JAKE'S VERY WELL-KNOWN FOR HIS LEADERSHIP IN THE FIELD, AND FOR HIS REMARKABLE CONTRIBUTIONS IN THE MOLECULAR CELLULAR BIOLOGY OF HEPATITIS B, AND ALSO STUDIES IN THE PATHOGENESIS OF PRIMARY LIVER CELL CANCER, WHICH HE'S GOING TO DISCUSS TODAY. OBAMA OUR SECOND SPEAKER, PROFESSOR AND CHAIRMAN OF THE DEPARTMENT OF SURGERY IN GEORGE TOWN, LYNT JOHNSON, A LEADER IN ORGAN TRANSPLANTATION FROM A CLINICAL AND INVESTIGATIVE STANDPOINT. PARTICULARLY IN EFFORTS TO DEVELOP MINIMAL INVASIVE TECHNIQUES, BOTH FOR TREATMENT AND FOR DIAGNOSIS. FOLLOWING HIS TRAINING, AT THE MASS GENERAL AND GRADUATED FROM HARVARD, HE WENT TO THE UNIVERSITY OF MARYLAND WHERE HE FOUNDED THE LIVER TRANSPLANT PROGRAM, AND IN 1998, MOVED TO GEORGE TOWN WHERE HE HAS FOUNDED THE GEORGETOWN TRANSPLANT IN STITUTE. BOTH OF OUR SPEAKERS ARE HIGHLY HONORED, RECOGNIZED, AND MANY A WARDS AND ALL OF THAT. SO WE'RE VERY GRATEFUL TO BOTH OF YOU AND JAKE, PERHAPS, YOU WOULD BEGIN. >> THANKS FOR THAT KIND INTRODUCTION. A GREAT PLEASURE TO RECONNECT WITH MY PARTNER IN CRIME, THE MOLECULE SCHOOL, DR. LYNT JOHNSON. BOTH WHO WERE MEDICAL STUDENTS, DIDN'T KNOW ANYTHING. BUT WANTED TO DO EVERYTHING. NOW WE ARE PROBABLY NOT MUCH BETTER. STILL DON'T KNOW A LOT. DIDN'T REALLY WANT TO DO ANYTHING ANYMORE, WE'RE TOO HOLD WE'RE LEAVING IT TO THE YOUNG PEOPLE TO MAKE MAJOR ADVANCES IN THE FIELD. I WANT TO ECHO THE MEMBERS ABOUT TOM, CERTAINLY A GIANT AND LEAD ER IN THE FIELD. JUST PASSED AWAY THIS YEAR. SO -- AND HE'S BEEN WIDELY RECOGNIZED IN THE LIVER FIELD AND ACTUALLY IN THE ANNUAL LIVER MEETING THERE IS A LECT SPECIFIC ALLY DEDICATED TO HIM, THE TOM STOSSEL LECTURE. I THINK MOST OF YOU SHOULD RECOGNIZE HIS CONTRIBUTION. HE WAS SUPPOSED TO SWITCH TO THIS ONE. IS HE BACK THEIR? SO I THINK LIVER CANCER IS ACTUALLY, IN MY MIND, REALLY A NEGLECTED CANCER. AND THEN WE HAVE A LOT TO LEARN ABOUT LIVER CANCER. AND WHAT I'M GOING TO DO TODAY IS REALLY TRY TO SHARE WITH YOU SOME OF THE STATE OF THE KNOWLEDGE ABOUT THE CLINICAL ASPECTS OF LIVER CANCER AND I'M CERTAINLY NOT GOING TO GO INTO GREAT DETAIL ABOUT THE TREATMENT DR. JOHNSON WILL PROBABLY GO INTO A LOT MORE DETAIL ABOUT DIFFERENT MODALITY TREATMENT. THEN WHAT I'M GOING TO DO, MOV ING TO TALK ABOUT SOME OF THE WORK WE HAVE BEEN WORKING ON, REALLY TRYING TO IDENTIFY CERTAIN MOLECULAR FOOTPRINTS, HOW THIS HEPATITIS C VIRUS CAUSED LIVER CANCER, AND THEN TRY TO MAYBE BRING THEM TOGETHER IN TERMS OF HOW CAN WE ADVANCE THE WHOLE FIELD, NOT ONLY UNDERSTANDING THE PATHOGENESIS HEPATITIS -- OF LIVER CANCER, BUT ALSO MAYBE TO ADVANCE TREATMENT THAT WE POTENTIALLY CAN DEVELOP MOLECULAR TARGET TO SOME OF THESE LIVER CANCERS. WOULD IT FURTHER ADO, IN CONTRAST TO MANY CANCER, WE CUE KNOW A LOT ABOUT LIVER CANCER. WE KNOW ABOUT WHAT CAUSES LIVER CANCER. WHAT THE CONDITION ASSOCIATED WITH LIVER CANCER, CLEARLY VIRAL HEPATITIS, BOTH C CB, C AND D. AND VARIOUS DIFFERENT TOXINS. ONE OF THEM THAT WE ALL ENJOY DRINKING IS ALCOHOL. SO EXCESSIVE ALCOHOL DRINKING CAN LEAD TO LIVER CANCER. ONE OF THE WELL-KNOWN CARCINOGEN HAS BEEN INPLIICATED, THIS IS MUCH MORE COMMON IN AREAS OF CHINA, WHICH IT'S CREATE PREVALENT. THERE OTHER TOXINS ASSOCIATED WITH LIVER CANCER. CERTAINLY, SOME METABOLIC DISEASES, FATTY LIVER DISEASE, CAN BE ASSOCIATED WITH LIVER CANCER. MANY OTHER CHRONIC LIVER DISEASE S, HEPATITIS iPRIMARILY CIRRHOSIS, DIFFERENT GENETIC DISEASES SUCH AS HEMOCHROMATOSIS , ALPHA 1, ACUTE PRO FEARIA. USUALLY, AT END STAGE OF THESE DISEASES WE CAN SEE LIVER CANCER IN THESE PARTICULAR DISEASE ENTITIES. FINALLY, I THINK JUST CIRRHOSIS IS A PREMALIGNANT FACTOR. SO CIRRHOSIS CAUSED BY ANY IDEOLOGY CAN BE ASSOCIATED WITH LIVER CANCER. THIS IS CERTAINLY RAISING A VERY IMPORTANT POINT ABOUT HOW THE PREMAGNIFICENT CONDITION, WHETHER IT'S INDUCED BY VIRAL HEPATITIS OR TOXIN OR ALCOHOL, YOU CAN REALLY HAVE THE COMMON PATHWAY TO FORMATION OF LIVER CANCER. AND LIVER CANCER IS ACTUALLY -- ON THE RISE IN THE U.S. AND THIS IS JUST A RECENT CANCER CONSTITUENTIC FROM 2016. THE LIST OF CANCER THAT IN TERMS OF PREVALENCE, YOU CAN SEE THAT LIVER CANCER, ONLY ABOUT -- LIST S NO. 13 IN TERMS OF THE NUMBER OF CASES PER YEAR, BUT IF YOU LOOK AT THE MORTALITY, IT'S RANKED NO. 5 OF 6 IN TERMS OF MORTALITY, LIVER CANCER. AND MORE IMPORTANTLY, ONE OF THE HIGHEST CASE FATALLY RATES. IF YOU'RE DIAGNOSED WITH LIVER CANCER, YOU'RE MORE LIKELY TO DIE FROM THE DISEASE THAN ANY OTHER CANCER. AND IF YOU LOOK AT GLOBALLY, LIVER CANCER ACTUALLY IS MORE PREVALENT, NUMBER 67 POSITIONS. AND IF YOU LOOK AT THE DEATH FROM CANCER, LIVER CANCER RANKED NO. 2, AGAIN, IN TERMS OF DEATH FROM CANCER WORLDWIDE. AGAIN, ALSO HAS A VERY HIGH CASE RATE OF 95%, SO -- WHICH IS REALLY QUITE ALARMING. IN LIGHT OF THESE PREVALENCE AND THIS INCREASED MORTALITY, CERTAINLY VERY IMPORTANT FOR US TO CONSIDER HOW CAN WE SCREEN FOR LIVER CANCER. UNFORTUNATELY, THIS AREA IS STILL CONTROVERSIAL. AND I'M JUST REALLY GOING TO SUMMARIZE WHAT THE ASLD GUIDELINE HAS RECOMMENDED IN TERMS OF SCREENING FOR LIVER CANCER. FIRST OF ALL, OBVIOUSLY, WE ONLY WANT TO SCREEN PEOPLE WHO HAVE HIGH RISK LIVER CANCER. AND THOSE ARE THE PEOPLE AS I MENTIONED TO YOU, PEOPLE ARE CHRONIC VIERO HEPATITIS, CIRRHOSIS, AND ALSO SUCH SER ROTESIS, ANY IDEOLOGY THAT CIRRHOSIS IS A PREMALIGNANT CONDITION. SO THERE ARE CERTAIN RATES, SUCH AS ASIAN, AFRICAN, AND AS WELL AS FAMILY HISTORY OF LIVER CANCER SHOULD BE IN THE HIGH RISK OF LIVER CANCER, SO THEREFORE, THESE PEOPLE, THE THRESHOLD FOR SCREENING THEM IS LOWER. THEY DON'T NECESSARILY HAVE TO HAVE CIRRHOSIS. IF THEY HAVE ANY KIND OF ETIOLOGY ASSOCIATED WITH LIVER CANCER SUCH AS VIRAL HEPATITIS, THEIR RECOMMENDATION IS YES, THEY SHOULD BE SCREENED. WHAT FEW SCREEN WITH? THIS IS VERY CONTROVERSIAL. ULTIMATELY EXTRA SOUND EVERY 6- 12 POUNDS. AND AFP, ALPHA FETA PROTEIN, NOT OFFICIALLY RECOMMENDED BUT STILL USED BY MANY PEOPLE. THE REASON IT'S NOT OFFICIALLY RECOMMEND, IT CARRIES A VERY HIGH OR LOW SENSITIVITY AS WELL AS SPECIFICITY IN TERMS OF DIAGNOSING LIVER CANCER. SO THEREFORE, IT'S NOT OFFICIAL LY RECOMMENDED. I STILL USE IT SOMETIMES. AND OTHER TESTS SUCH AS [INDISCERNIBLE], L3 FRACTION OF SFP. SPECIAL TESTS DEVELOPED TO IM PROVE THE SENSITIVITY AND SPECIFICITY OF DETECTING LIVER CANCER. HOUR, THEY HAVE NOT REALLY PROV EN TO BE ANY BETTER THAN THE SCREENING MODALITYTY OF ULTRASOUND EVERY 6-12 MONTHS. AND THIS -- A LOT OF INTEREST IN TRYING TO IDENTIFY MILE MARKERS, MOLECULARLY OR WHATEVER TECHNOLOGY THAT PEOPLE ARE INTERESTED IN, SO THEREFORE, CAN GIVE A LEG UP IN TERMS OF DIAGNOSING THE CANCER IN MUCH EARLIER STAGE. SO OBVIOUSLY, AS YOU ALL REALIZE , THAT THE REASON WE SCREEN, BECAUSE WE BELIEVE THAT IF WE IDENTIFY INDIVIDUALS WITH CERTAIN CANCER, WE CAN KILL THEM THAT'S THE REASON WE SCREEN. THAT GETS TO THE POINTS AT A WHAT ARE THE MODALITY OF TREATMENTS? DO WE HAVE EFFECTIVE TREATMENT? UNFORTUNATELY, WE DO AND WE DON'T. REALLY DEPENDING ON THE SITUATION. SO THIS IS REALLY WHAT I'M GOING TO TALK ABOUT NEXT PREVIOUSLY. I'M GOING TO LEAVE DR. JOHNSON TALK MORE ABOUT THAT. BUT I THINK SUFFICE TO SAY, PROBABLY THE TAKE HOME MESSAGE, THE TREATMENT STRATEGY IS BASED ON THE STAGING OF THE LIVER CANCER. AND BASED ON SO-CALLED BARCELONA LIVER CARP STAGING FROM 0 TO D, AND THESE ARE STAGINGS BASED ON THE SIZE, THE NUMBER, THE VASCULAR INVASION, AS WELL AS METASTASES. SO OBVIOUSLY, THE LOWER STAGE YOU HAVE, THE SMALLER THE CANCER , THE FEWER NUMBER OF CANCER YOU HAVE. WHEN YOU GET TO THE STAGE B, THAT'S PRETTY MUCH THE END STAGE LIVER CANCER. SO THE TREATMENT IS REALLY BASED ON THE STAGE. EARLY STAGES, SURGERY, AN LAYINGS, TRANSPLANT RECOMMENDED. FOR INTERMEDIATE STAGE, STAGE B, TRANSARTEALIAL CHEMO EMBOLIZATION IS ENCOURAGED. STAGE C, WE DO HAVE A MOLECULAR TARGET DRUG, SORE -- SORE [TECHNICAL DIFFICULTIES]. THE ONLY APPROVED DRUG FOR TREATMENT OF LIVER CANCER AT THE END STAGE. WHEN YOU GET TO STAGE D, UNFORTUNATELY, THERE IS NOT MUCH YOU CAN DO, REALLY, THE SPIT SUPPORTERIVE CARE IS THE BEST ROUTE. AGAIN, THESE MODALITIES, JUST RECOMMENDATIONS. A LOT DEPENDS ON THE TUMOR BURDEN, LIVER FUNCTION, BASELINE LIVER FUNCTION, PERFORMANCE STATUS OF INDIVIDUALS, AND SO WE LOOK AT VARIOUS DIFFERENT SORT OF -- OTHER STAGINGS JUST AS CLASS, LOOKING AT DIFFERENT ECOG PERFORMANCE STATUS, ALSO CONSIDER OBVIOUSLY ABSENCE OF SEVERE CO-MORBIDITY IN ORDER TO DECIDE THE BEST TREATMENT MODALITY. IN THE NEXT SLIDE, AGAIN, TAKEN FROM THE ASLD GUIDELINE. THIS IS TO PROVIDE YOU WITH MORE OF THE DETAILED TREATMENT ALGORITHM, DEPENDING ON THE STAGES OF VARIOUS DIFFERENT STAGES OF CANCER. THIS TELLS YOU DO AND DON'T TYPE OF THINGS AND THE BOTTOM IS THE VERY DIFFERENT TREATMENT MODALITYTY. THE WHOLE IDEA, THIS IS TAILORED TO THE INDIVIDUAL STAGE. SUFFICE TO SAY THAT IF WE DO DETECT THE CANCER EARLY, YOU CAN EFFECTIVELY CURE THE INDIVIDUAL OF LIVER CANCER, SO FOR INSTANCE , IF YOU IDENTIFY SINGLE NODULE SURGERY ACTUALLY WORKS PRETTY WELL. LIVER TRANSPLANT AS WELL. SO REALLY, AT THE EARLY STAGE, WE CAN ACHIEVE CURATIVE THERAPIES. I THINK THAT'S IMPORTANT KEEP IN MIND. VERY OFTEN WHEN WE DIAGNOSE THESE PATIENTS THEY TEND TO BE IN THE MIDDLE LATE STAGE. I THINK THAT'S THE AREA IN TERMS OF BEING ABLE TO EFFECTIVELY AND -- EFFECT IVELY IDENTIFY INDIVIDUALS WITH LIVER CANCER AT THE EARLY STAGE BECAUSE WE CAN CURE THESE PEOPLE WITH VARIOUS DIFFERENT MODALITYIES. SO THE PATHOGENESIS OF LIVER CANCER, I THINK, AS I MENTIONED PREVIOUSLY, IT'S -- THE VERY DIFFERENT ETIOLOGIC AGENTS. AND IN THE CONTEXT OF VARIOUS ENVIRONMENTAL FACTORS, THE GENETIC PREDISPOSITIONS, MET ABOLIC DYSFUNCTIONS, AND IN -- WITH INFLAMMATORIES, IMMUNE DEREGULATION, ALL THESE CONTRIBUTE TO THE INFLAMMATORY OF LIVER CANCER. LIVER CANCER ACTUALLY IS A PROGRESSIVE PROCESS. IT BEGINS REALLY IN A HEALTHY LIVER, WHEN YOU HAVE AN INSULT ING AGENT SUCH AS BIO HEPATITIS LEAD TO SERIOUS INFLAMMATION CAUSING FIBROSIS AND DAMAGE TO THE LIVER. VALUELY RESULTING IN CIRRHOSIS. THAT'S WHERE THE LIVER CANCER A RISES, MOST OF THE TIME. NOT ALL TOO THE TIME. IT CAN ARISE IN A RELATIVELY HEALTHY LIVER. BUT GREATER THAN 95% OF THE TIME LIVER CANCER ARISES IN THE SETTING OF CIRRHOSIS. SO THIS IS IMPORTANT BECAUSE LIVER CANCER ARISE IN A DISEASE ORGAN AS OPPOSED TO MANY OTHER CANCERS WHICH JUST HAPPEN, NOT BECAUSE IT'S UNDERLYING DISEASE, IT JUST HAPPENED. SO THIS IS A HIGHLY CORRELATED PATHOGENIC PROCESS. SO THERE HAVE BEEN A LOT OF INTEREST IN IDENTIFYING THE GENETICS OF LIVER CANCER AND I'M NOT REALLY GOING IN GREAT DETAIL CERTAINLY PEOPLE AT NCI HAVE MADE MAJOR CONTRIBUTIONS, IDENTIFIED THE GENETIC CHANGES ASSOCIATED WITH LIVER CASH. I WOULD SAY THERE ARE CERTAIN DRIVER GENES IDENTIFIED USING VARIOUS GENETIC TECHNIQUES, THESE ARE THE VARIOUS GENES SHOWN TO BE HIGHLY PREVALENT, MUTATE HIGHLY EXPRESSED ACTIVATE ED. FINALLY, NRF2, RELATED TO OXIDATIVE INJURY PATHWAY. THESE HAVE ALL BEEN SO-CALLED THE DRIVER GENES. THESE ARE THE GENES FREQUENTLY MUTATED IN LIVER CANCER. [INDISCERNIBLE] AND FRIENDS HAVE PUT TOGETHER THIS GENETIC LANDSCAPE, AND BIOMARKERS OF HCC SORT OF A NICELY ILLUSTRATED VERY DIFFERENT ETIOLOGICAL AGENT AS I ALLUDED TO PREVIOUSLY, ON THE TOP. AND THEN WHEN SHE WAS ABLE TO KIND OF -- LOOKING AT THE VAR IOUS DIFFERENT GENETIC ALTERATIONS OF ALL THE DIFFERENT ETIOLOGICALLY RELATED LIVER CANCER, AND WHAT SHE HAD NOTICED , THAT THERE IS CERTAINLY DISTINCT BUT SOMETIMES OVERLAP PING GENETIC DEFECTS. FOR EACH TYPE ITLANGUAGAL AGENT, THIS IS SOMEWHAT OF A UNIQUE GENETIC SIGNATURE ASSOCIATED WITH THAT TYPE OF CANCER. SO THIS IS INTERESTING IN A SENSE THAT THEY REALLY HAVE DIFFERENT IDEOLOGICAL PROCESS THAT CAUSES LIVE CANCER. BY LOOKING AT THE GENETIC LANDSCAPE, WE COULD GET A SENSE OF THESE CANCERS ARE VERY DIFFERENT. NOT ALL LIVER CANCERS ARE THE SAME. VERY QUIET HETEROGENOUS DISORDER S. BUT WE HAVE WAYS TO INTERVENE. SO WHAT I'M GOING TO SHARE IS TALKING ABOUT HEPATITIS C. CERTAINLY, WE HAVE A CURATIVE DRUG. SO THE BIGGEST QUESTION IS WHAT IS THE RISK OF LIVER CANCER IN H CC PATIENTS WITH SUSTAINED VIR OLOGICAL RESPONSE TO THESE DRUGS. STUDIES HAVE SHOWN THAT A HCV PATIENTS WITH SVR HAVE A REDUCED RISK OF LIVER CANCER. THIS IS ONE OF THE DATA OF ONE OF THE LARGE STUDIES. BRUNO ET AL FOLLOWED A LARGE NUMBER OF PATIENTS TREATED FOR HEPATITIS C, AND THOSE -- CERTAINLY THEY ARE A GROUP OF PATIENTS THAT HAD NO RESPONSE, CALLED NO SVR. COMPARED WITH SDR OVER LONG RANGE FOLLOW-UP WITH REGARDS TO LURCH REPLATED COMPLICATION OR LIVER CANCER. YOU CAN SEE THAT THESE TWO CURVE S ARE A DIVERSION, THOSE THAT HAD SVR HAVE DECREASED OF RIVER RELATED COMPLICATION, AS WELL AS LIVER CANCER. AND THIS HAS BEEN VALIDATED MANY OTHER LARGER STUDIES AS WELL, FOLLOWING PATIENTS THAT RESPOND ED TO LIVER CANCER. BUT, IF YOU LOOK AT SORT OF THE LONG TERM FOLLOW-UP, YOU CAN SEE THAT THE LIVER CANCER RATE OF THOSE RESPONDED TO THE TREATMENT ACTUALLY ARE CREEPING UP. ALMOST CATCHING UP TO THOSE WHO HAVE SVR. SUCH LONG TERM INCREASE IN TERMS OF -- NOT INCREASE, BUT CERTAINLY INCREASE IN -- OVER THE BASELINE, LIVER CANCER HAS BEEN VAL DATAD BY STUDIES THAT HAVE LOOKED AT THESE PATIENTS, NOTICED THAT THEY STILL ARE ON THE RISK OF LIVER CANCER. SO BEFORE I'M GOING TO TALK MORE , I WANT TO KIND OF MAYBE INTRODUCE SEVERAL CONCEPTS TO YOU ABOUT VIRUS IN CANCER. I THINK THAT'S IMPORTANT TO KNOW A LOT OF PEOPLE THINK THAT THE VIRUS, HEPATITIS VIRUS CAUSES CANCER, ACTUALLY 0 THAT'S NOT TRUE. THAT'S NOT THE PURPOSE OF VIRUS AND CANCER. IT'S TO PROPAGATE IN ITS INFECT ED HOST. AND THE VIRUS HAS EVOLVED TO EXPLOIT AND MODULATE HOST FUNCTIONS FOR PROPAGATIONS. VIRUS HAS EVOLVED MULTI MECHANISMS TO COUNTERACT HOST ANTVIRAL RESPONSE. VIRAL INDUCED DISEASE IS A RESULT OF HOST RESPONSE TO VIRAL INFECTION. THIS IS PRETTY MUCH VIRAL INFECTION, ALTHOUGH CERTAIN VIRUS CAN CAUSE DIRECT INJURY TO THE CELLS, BUT VERY OFTEN IT'S THE INJURY RELATED INFLAMMATION CAUSING SIGNIFICANT MOBILITY AND MORTALITY ASSOCIATED WITH VIRAL INFECTION. FOR INSTANCE, EBOLA. IT CAN KILL A LOT OF CELLS BUT THE INFLAMMATORY RESPONSE THAT CAN KILL YOU. SO THAT'S A VERY IMPORTANT LESSON. FINALLY, RELEVANT TO THIS TALK, VIRAL ASSOCIATED CARCINOGENESIS IS A SECONDARY PARAFFIN, UNIN TENDED PRODUCT OF VIRAL INFECTION. THE VIRUS IS NOT THERE TO CAUSE CANCER. CANCER ONLY OCCURRED BECAUSE OF ALL THESE OTHER -- A BYPRODUCT. SO THESE ARE IMPORTANT CONCEPTS I WANT TO CONVEY TO YOU AS WE TALK ABOUT HCV INFECTIONS. SO THIS IS A LIFE CYCLE MAP OF H CV, SUSCEPTIBLE CELLS, A HEPATITIS HE PAT SITE SEQUENTIAL PROCESS. VIRAL ENTRY TO THE CELLS, UNCOD ING OF THE VIRAL GENOME. MOVE TO ER TO PRODUCE VIRAL PROTEINS. AND THEN FROM THERE, REPLICATION OCCURS. AND THEN WHAT'S UNIQUE IS THAT ACTUALLY IT TAKES ADVANTAGE OF THIS UNIQUE ORGANIZATIONALS IN THE PATCYTES WHERE THE VIRUS ACTUALLY ASSEMBLES. I'LL COME BACK TO THIS. THIS IS A STEP FOR THE VIRUS TO SUCCESSFULRY REPLICATE AND PRO DUCE NICHES VIRUS -- IN EFFICIENCY INFECTIOUS VIRUS. HUNDREDS, IF NOT THOUSANDS OF CELLULAR PROTEIN THAT INTERACT WITH THE VIRUS FOR THESE THINGS TO HAPPEN. ALSO VARIOUS DIFFERENT GENETIC METASTASES CHANGES GOING ON WHEN THE CELL SENSE OF THE VIRUS IS GOING. IN ADDITION, THERE ARE A LOT OF, AS YOU KNOW, VIRUS INFECTION IN DUCED IMMUNE RESPONSE, SO THERE ARE A LOT OF INTERACTIONS BETWEEN THESE PARTICULARLY IF INFECTED CELLS AND THE REST OF THE BODY. THIS IS IMPORTANT IN CONTEXT OF HOW THIS CAUSED DISEASE. SO FRANKLY, IN THE LAB OVER THE YEARS, HAVE -- USING VERY DIFFERENT GENOMIC TECHNOLOGY TO GENERATE A COMPLETE -- I WON'T SAY COMPLETE, BUT CERTAINLY AS MUCH AS WE KNOW IN TERMS OF VIRAL CELL INTERACTION. AND THESE ARE THE LIST, VARIOUS DIFFERENT CELLULAR FACTORS IN THERE. EITHER THEY ARE LINKED TO VAR IOUS DIFFERENT STEPS, VIRAL REPLICATION FROM ENTRY. REPLICATION TO ASSEMBLY, AND DIFFERENT LOCATION. AND THIS IS JUST SORTS OF A MAP JUST TO SHOW YOU HOW COMPLICATED , HOW DOES THE VIRUS -- THE VIRUS NEEDS TO REPLICATE IN THE CELLS. YOU NEED TO TAKE ADVANTAGE OF THESE CELLS OR MACHINERY FOR REPLICATIONS. SO I'M GOING TO USE THIS MAP TO SHARE SOME OF THE PARTICULAR PATHWAYS THAT WE HAVE MAPPED OUT AND HOW THEY RELATED, NOT ONLY TO SUPPORT THE VIRAL INFECTION, BUT ALSO POTENTIALLY INDUCE PRE MALIGNANT CONDITION OF INFECT ED CELLS THAT WILL -- THAT COULD LATER PROGRESS TO LIVER CANCER. SO ONE OF THE PROTEINS IS IKK ALPHA. CHUCK INHIBITER OF NF-kappaB KINASE. AND YOU ALL PROBABLY KNOW WHAT NF-kappaB, A MAJOR REGULATORY PATHWAY IN THE CELLS. AND IT'S CONTROLLED BY A MASTER REGULATOR OF IKK COMPLEX. THAT'S THIS MULTI COMPLEX HERE. UPON INFLAMMATORY STIMULI, THE I KK COMPLEX IS PHOSPHORYLATELET ED. LEADING TO PHOSPHORYLATION OF B. IT'S THE PROTEIN THAT SEQUESTERS THE ACTIVE TRANSCRIPTION COMPLEX WHEN YOU PHOSPHORYLATE, IT LEADS TO DEGREEGATION OF THE NF-kappa B, RELEASING THE ACT IVE COMPLEX INTO THE NUCLEUS TO ACTIVATE TRANSCRIPTION. SO THE IKK IS THE CYTOPLASM, RIGHT? AND VIRUS CAN ACTIVATE THIS COMPLEX THROUGH VARIOUS DIFFERENT RECOGNITION RECEPTOR, SUCH AS [INDISCERNIBLE]. AND THIS -- NF-kappaB RYE SPOKESPERSONS IS PART OF THE ANTIVIRAL RESPONSE TOGETHER WITH OTHER HOST FACTORS CAN LEAD TO THE INDUCTION OF INTERFERON RESPONSE. AND I HAVE IKK COMPLEX, THE BETA AND GAMMA, CANNONICAL SUBUNIT. IKK ALPHA IS NOT REALLY NECESSARY BUT IT'S THERE. NOBODY KNOWS WHAT IT REALLY DOES THIS IS SOMETHING INTERESTING TO US. OBVIOUSLY, WE INVESTIGATE FURTHER INTO THESE PARTICULAR GENES. WHAT FRANK IS ABLE TO DO IS LINK THIS PARTICULAR GENE TO LIPID DROPLET FORMATION. WHERE THE VIRUS ASSEMBLES. AND THIS CONFOCAL MICROSCOPY BASICALLY SHOWS STAINING FOR LIPID DROPLET AS WELL AS CORE. WE KNOW FOR A LONG TIME THAT THE VIRUS REPLICATES OR ASSEMBLES IN THE DROPLETS. YOU CAN SEE VERY NICELY A SET OF SIGNAL WHEN YOU MERGE THEM TOGETHER. AND WHAT HAPPENED WHEN YOU SILENCED IKK ALPHA EXPRESSION? YOU CAN SEE THAT THE LIPID DROP LET FORMATION IS SIGNIFICANT LY REDUCED, AND ALTHOUGH THERE IS STILL SOME CORE PROTEIN, THEY NO LONGER CO LOCALIZE. SO THIS INDICATES THAT THE LKK ALPHA INVOLVED IN THIS PROCESS, WE DIDN'T KNOW THE CONNECTION BUT CLEARLY, WE KNOW LIPID DROP ARE THE IS IMPORTANT FOR VIRAL ASSEMBLY. ALSO I MENTIONED BEFORE, THE IKK ACTS IN THE CYTOPLASM BY PHOSPHORYLATEING THE IKK COMPLEX IC ALPHA CAN GO THROUGH THE NUCLEUS, AND THIS IS JUST EXPERIMENT. FRANK HAS SHOWN WHEN HE DEMONSTRATED THAT IN HCV INFECT ER CELLS DEMON TRAITED BY STAINING WITH CORE, AND LOOKING AT USING PARTICULAR SOFTWARE TO COMPARE WHAT'S UNINFECTED CELLS VERSES INFECTED CELLS, AND LOOKING AT THE SIGNAL OF IKK ALPHA IN THE NUCLEUS. THIS IS JUST A LINEAR DIAGRAM USING THE ZEN SOFTWARE SHOWING FROM UNINFECTED CELL TO INFECTED CELL, THIS IS A SIGNIFICANT IN CREASE IN THE NUCLEAR SIGNAL OF IKK ALPHA, WHICH CAN BE QUANTIFIED BY COUNTING A LOT OF THESE NUCLEI, SHOWING THAT HCV INFECTED CELL IS A PARTICULAR NUCLEAR LOCALIZATION OF IKK ALPHA. THE FIRST THINGS THAT COMES TO OUR MIND IS TO HAVE A TRANSCRIPTIONAL EFFECT. AND TO STUDY THIS, FRANK SET UP THIS PARTICULAR EXPERIMENT TO LOOK AT THE TRANSCRIPTOME MICRO ARRAY GENE EXPRESSION ANALYSIS. HE SET UP 4 CONDITIONS, CONTROL, TRANSEFFECTER CELL, AGAINST KENNEDY CENTER ALPHA AND THESE TWO CONDITION IN THE PRESENCE OF HCV INFECTION. THESE ARE THE FOUR CONDITIONS HE SET UP AND ANALYZED GENE EXPRESSION. AND WHAT HE FIRST SAW, IN THIS COLUMN SHOWS THAT THERE IS A SIGNIFICANT UP-REGULATION OF VAR IOUS LIPID METABOLISM GENES. IN THE PRESENCE OF ALPHA, HE SAW A SIGNIFICANT DIMINUTION. EITHER IN A -- IN NON HCV INFECT ER CELL OR -- SUGGESTING THAT IT PLAYS A CRITICAL ROLE IN TERMS OF LIPID GENE EXPRESSION. OF THIS, SIB1 AND 2, WHICH ARE THE 2 MASTER REGULATORS OF LIPID DROPLET TRANSCRIPTIONS WERE PARTICULARLY UP-REGULATED IN THE PRESENCE OF HCV, AS YOU CAN SEE HERE. AND THEN THAT CAN BE AGGREGATED BY KNOCKING DOWN THE IKK ALPHA. SO IN THE SAME TIME THAT [INDISCERNIBLE] WORKING WITH FRANK TOGETHER IN THE LAB WAS INTERESTING, THIS OTHER PARTICULAR PROTEIN, THE DDX3, A DEAD BOX POLY PEPTIDE 3 PROTEIN, AND THIS IS PROTEIN ALSO IN VOLVED. YOU CAN SEE THAT THE CLUSTERING INVOLVED IN THE ASSEMBLY OF THE VIRUS, AND ALSO, THIS IS BELONG ED TO A CLASS OF A HILO CASE IN WHICH MANY OF THESE PATENT RECOGNITION RECEPTOR, SUCH AS [INDISCERNIBLE] IS A MEMBER OF. WITH THAT IN MIND I WON'T GO THROUGH GREAT DETAIL. THIS IS A HYPOTHESIS WE MUCH, THAT HCV THROUGH IS PAMP ASSOCIATED, ACTIVATE THIS HILO CASE PATHWAY. THAT LEADS TO INTERFERON ANTI- VIRAL GENE INDUCTION, THAT TYPICALLY NEED TO -- LEAD TO A REDUCTION OF VIRAL REPLICATION. BUT IN PARALLEL WHAT THE VIRUS IS DOING, TAKE ADVANTAGE OF DIFFERENT PATHWAYS THROUGH THE D DX3, AND THE STRESS JANELLE. THAT'S WHERE IKK ALPHA IS ACTIVATED. THAT GOES TO THE NUCLEUS TO IN DUCE THE TRANSCRIPTIONAL PROGRAM TO ENHANCE LIPID DROPLET FORMATION IN ORDER TO FACILITATE VIRAL ASSEMBLY. SO THIS IS GREAT. THIS IS WHAT THE VIRUS WANTED TO DO. BUT THE CONSEQUENCE OF THIS IS THAT THIS LIPOGENIC, LEADS TO DISREGULAR LIPID METASTASES, WHICH HAS BEEN LINKED TO SO-CALLED LIPOTOXICITY, ONE OF THE MAJOR MECHANISMS OF FATTY LIVER DISEASE CAUSING LIVER CANCER. THIS IS HOW THIS CAN BE ASSOCIATED WITH LIVER CANCER. SO VIRUS NOT REALLY DOING THIS, CAUSING CANCER. BUT JUST MONKEYING AROUND, BECAUSE IT NEEDS TO, CAUSING THESE DISREGULATED PROCESS. THE SECOND THING I WANTED TO SHARE WITH YOU IS THE E-KADHERIN , AN ENTRY FACTOR. THIS IS LED TO TWO WELL-KNOWN ENTRY FACTORS. AND HOW DOES -- WHAT IS E-CAD HEREIN? IT'S A CONJUNCTION PROTEIN, HAS MANY DIFFERENT FAMILIES VERSES NECKENS. AND IT'S INVOLVED IN SELF-POLAR ITY, OR GANO GENESIS. THE LOSS OF IT IS ASSOCIATED WITH MALIGNANT FRAN TOREMATION, EPITHELIAL TO MESENCHYMAL TRANSITION, ALSO INVOLVED IN SIGNAL TRANSDUCTION. AND HAS BEEN SHOWN, THERE IS A TARGET OF MICROBIAL INVASION AS WELL. THIS IS A SUMMARY THAT I -- A FIGURE THAT I TOOK FROM THIS REVIEW ARTICLE WRITTEN BY CHARLIE RICE. THIS -- ACTUALLY, WE KNOW HOW THE VIRUS GET INTO THE CELLS. SO IF YOU LOOK AT THESE VERY DIFFERENT FACTORS, THEY BIND TO HEPARIN SULFATE. INTERACT WITH MANY OTHER CELL ULAR PROTEINS. AND THEN GETS MOVED TO SORT OF THE INTERCELLULAR EGYPTIAN WHERE [INDISCERNIBLE] 1 SHOWN HERE BECOMES INVOLVED. SO THIS IS A PATHWAY, SO ONCE THIS HAPPENS, THE VIRUS CAN ENTER THE CELLS IN A VESICLE, ENDOSIGHT TOTIC PROCESS. THEN THE VIRAL GENOME GETS RELEASED. WHAT IS THE ROLE? OF THE INTERCELL JUNCTION PROTEIN? WHAT IS THE ROLE IN TERMS OF VIRAL PATHWAY? SO THIS IS REALLY SHOWN BY SOME CONFOCAL STUDY THAT FRANK DE. THIS IS AN IMAGE SHOWING THE CO LOCALIZATION OF E CAD HEREIN. YOU CAN SEE THAT. THESE ARE THE SUSTAINING, THE RED. THEY'RE ALL OBVIOUSLY SHOWING THE DISTRIBUTION ON THE CELL SURFACE. VERY NICE LOCALIZATION, COLOCAL IZATION. SOME OF THE AREA. BUT WHEN YOU KNOCK DOWN THE E CAD HEREIN, STAIN THEM, YOU SEE THAT STAINING OF [INDISCERNIBLE] BECOMES DESHOVELED, NOT REALLY LOCALIZED WHERE THEY'RE SUPPOSED TO BE. THEY'RE NO LONGER COLOCALIZED TOGETHER BECAUSE THE CDH1 IS NO LONGER THERE. SIMILARLY, IT WAS -- IF YOU KNOCK OUT CDH1 YOU CAN SEE THAT THE DISTRIBUTION OF [INDISCERNIBLE] IS TOTALLY DISTURBED. NO LONGER COLOCALIZED. HOWEVER, IF YOU LOOK AT ANOTHER SO-CALLED TIGHT JUNCTION PROTEIN , THERE IS NO EFFECT. SEEMS LIKE THE FACT THAT WE SEE SPECIFIC HERE, SPECIFICALLY CORRELATED TO A FACT THE DISTRIBUTION OF [INDISCERNIBLE]. BUT NOT OTHER TIGHT JUNCTION PROTEINS. THIS IS JUST -- THIS IS A SUMMARY. SO ANOTHER THING WHAT HCV DOES, DOWNREGULATES E CAD HEREIN. IF YOU FOLLOW FROM LEFT TO RIGHT WITH A DIFFERENT TIME COURSE, FROM TIMES 0 TO 72 HOURS, AND STAINING BY CORE PROTEIN, RED, AND eCODE HEREIN GREEN, AS INFECTION PROGRESSES, THE IMPRESSION IS GRADUALLY DECREAS ED, ESPECIALLY IN THE CELLS THAT EXPRESS STRONGLY POSITIVE CORE. SO H.CV IS ACTUALLY DOWN REGULATE EXPRESSION. THIS IS SHOWN BY WESTERN BLOT. IF YOU LOOK AT THE TIMING, THE SIGNIFICANT REDUCTION OF LEVEL. BUT ON THE OTHER HAND, IF YOU LOOK AT ANOTHER CELLULAR MARKER, SUCH AS [INDISCERNIBLE], IN CREASES. IN THIS, THE CONTRASTING EXPRESSION PEN IS CONSISTENT WITH EPITHELIAL TO MESENCHYMAL TRANSITION, A HAUL MARK OF MALIGNANT TRAN FORMATION. WHAT DOES E CAD DO? IT REGULATED DISTRIBUTION OF CLD N1, TO INTERACT WITH HCV EFFECTIVELY. AND VIRUS ACTUALLY WOULD DOWN REGULATE IN ORDER TO DIS REGULATE THIS DISTRIBUTION, REALLY, AS EFFORT TO PREVENT SUPER NICHES INFECTIONS. SO THEREFORE BY DOWNREGULATING E CAD YOU CAN PREVENT OTHER VIRUS. BUT THE CONSEQUENCES IS LINKED TO DOWNREGULATION EVIDENT E CAD IS LINKED TO EP PEELIAL MESENCHYMAL TRANSITION, ONE OF THE FEW STEPS LEADING TO LIVER CANCER. SO THE THIRD I WANT TO SHARE WITH YOU IS RELATED TO THIS PARTICULAR OTHER PROTEIN THAT FRANK IDENTIFIED IN THIS MAP. IT'S SMAD, A SIGNALING MOLECULAR , AND INVOLVED IN TRANSPORTATIONAL REGULATORS. WHAT IS A SMAD? PARTICULARLY, 6 BELONGS TO A FAMILY OF SIGNAL TRANSDO YOU UNDERSTANDS, BETA FAMILY SIGNALING. IT PLAYS A CRITICAL ROLE IN MANY DIFFERENT CELLULAR PATHWAYS. THE SMAD6 AND 7 ARE INHIBITORY. THEY'RE INDUCED BY BETA SIGNALING, A FEEDBACK INHIBITOR BLOCKING THE OTHER SIGNALING REGULATORY SMAD PATHWAYS. THAT'S WHAT IT SAYS. AND THEN ALSO, SMAD HAS BEEN IMPLICATED TO HAVE DIRECTION TRANSCRIPTIONAL ACTION. AND THAT'S TOTALLY INDEPENDENT FROM THE OTHER SMAD. THIS IS INTERESTING TO US ECONOMY SMAD -- WHETHER 6 PLAYS A ROLE REGULATING ENTRY. SMADS WILL UPREGULATE, OR REGULATE EXPRESSION HEPARIN SULFATE ON THE CELL SURFACE. AS I MENTIONED BEFORE, HEPARIN SULFATE, CELL SURFACE, THE FIRST MOLECULAR THE VIRUS ENCOUNTERS. IT REGULATES THE CELLULAR LEVER OF HEPARIN SULFATE SHOWN BY THE STAINING WITH ANTIBODY AND THIS ALSO BE CORBRATED BY SCAN AGAINST THIS HEPARIN SULFATE PROTEIN YES GLYCAN LOOKING AT CONTROL CELLS OR SILENCE CELL. THERE IS A SIGNIFICANT REDUCTION OF HEPARIN SULFATE PROTEOGLYCAN LEVEL WHEN YOU SILENGTHS LENS. IT CONSISTS WITH THE PROTEO GLYCAN, A CORE PROTEIN WHICH ALL THE GLYCOSYLATED. SO WAS ABLE TO LOOK AT THE PARTICULAR CORE PROTEIN EXPRESSIONS. THESE CORE PROTEINS WERE SIGNIFICANTLY REDUCED WHEN YOU SILENCE IN THIS PARTICULAR SITUATION. SO THIS SHOWS THAT HEPARIN SULFATE IS REGULATED BY SMAD 6. THIS IS ONE OF THE INTERESTING OBLIGATIONS THAT COMES FROM THE LIPID METASTASES -- METABOLISM FIELD. IT PLAYS A CRITICAL ROLE IN TERMS OF LIPID PROTEIN TRANSPORT , TRANSPORTING CHOLESTEROLS IN ADDITION TO OTHER KNOWN VIRAL -- OTHER KNOWN DLR RECEPTORS. SO FRANK SHOWED THAT BY REGULAT ING THE HEPARIN SULFATE SMAD 6, REGULATED THE LIPID TRANSPORTER. THIS IS TO SHOW THAT -- I'M SORRY. SO ACTUALLY THIS IS LIKE -- THE PREVIOUS SLIDE. I GUESS IT DIDN'T SHOW UP WELL. WHAT ALSO I WANT TO SHOW YOU, HC V INFECTED CELLS, INCREASE IN SMAD 6. THIS SHOWS YOU THE THE WESTERN BLOCK THAT EVEN IN LIVER BIOPSY, THE SMAD 6 LEVEL ARE SIGNIFICANT LY INCREASED. I DON'T KNOW WHAT HAPPENED TO THE PREVIOUS SLIDE. ANYWAY, SO THIS IS REALLY JUST SUMMARIZE THE FACT THAT WHAT HCV INFECTIONS IS DOING TO THE CELLS WHEN THE VIRUS IS GETTING TO THE CELLS, THROUGH THE NF-kappaB PATHWAY WHICH I DON'T HAVE TIME TO SHOW, ONE OF THE UP REGULATED SMAD 6/7 EXPRESSION. THE 6 GOES TO THE NUCLEUS TO UP REGULATE THE RECEPTOR. THIS IS TRYING TO NOT ONLY IN CREASE THE VIRAL ENTRY PATHWAY , BUT ALSO TO FACILITATE TRANSPORT OF THE LIPOPROTEIN, QUITE FAVORABLE TO THE VIRUS. THAT'S WHAT THE VIRUS WANT TO DO , ENHANCE THE LIPID METABOLISM IN THE CELLS TO SURVIVE. THIS IS ANOTHER WAY HOW THE VIRUS IS SUPPORTING A CELL. BUT ON THE OTHER HAND, AS I MENTIONED TIE, SMAD 6 AND 7, WHAT IT DOES IS TO BLOCK THE BET A PATHWAY. IF YOU UPREGULATE THIS IT WILL BLOCK THE PATHWAY. IT PLAYS A CRITICAL ROLE IN TERMS OF CONTROLLING THE PROLIFERATION OF HEPATOCYTES. IF YOU BLOCK THE ROLE THE CELL IS LIKELY TO PROLIFERATE ABOUT A CHECK. THAT'S REALLY ONE OF THE CONDITIONS THAT SIGNALING PERHAPS THE CELL IN THE PRE MALIGNANT STAGE, SO I THINK AGAIN THE VIRUS IS NOT THERE TO BLOCK THE TGF PATHWAY. IT DOES IT BECAUSE IT WANTS TO UP-REGULATE [INDISCERNIBLE] FOR ITS OWN SURVIVAL. BUT THE CONSEQUENCES OF THAT IS CAUSING SOME BISTANDING EFFECT OF TGF BETA PATHWAY, AFFECTING THE [INDISCERNIBLE]. SO THE LAST VIGNETTE I WANT TO SHARE IS THIS OTHER PROTEIN ALSO INVOLVED CALLED N-MCY DOWNSTREET REGULATED GENE 1. WHAT NDRG1? IT'S A ALPHA FAMILY, LACKSCALITY LYTIC CAPACITY. WHAT'S IMPORTANT, IT SUPPRESSED BY MIC. I TOLD YOU BEFORE, A MAJOR DRIVER GENES IN LIVER CANCER. AND ALSO, A LOT OF EVIDENCE SUGGESTED THAT NDRG1 IS A TUMOR SUPPRESSER GENE. LOSS EXPRESSION GENE IN MANY LIVER CANCER TYPES, IF YOU LOOK AT ALL THESE DATABASE. NDRG IS ONE OF THE GENES IMPLICATED AS A TUMOR SUPPRESSER GENE. AND IT CAN BE INDUCED BY VARIOUS DIFFERENT CELLULAR STRESS SIGNALING, HEAVY METAL, HYPOXIA, INVOLVED IN CELL PROLIFERATION, CANCER METASTASES, SO IT DOES A LOT OF DIFFERENT THINGS. WHAT'S CRITICAL, REGULATED BY MY C. IN OUR MODEL, YOU CAN LOOK AT -- WHEN YOU LOOK FOR NDRG1 EXPRESSION, IT DOWNREGULATESES N DRG EXPRESSIONS. THIS WOULD BE VAL INDICATED USING A DIFFERENT ANTIBODY LOOKING AT THE PHOSPHORYLATE ACT IVE FORM. SO WHAT IS -- WHAT DOES IT DO IN THE HCD INFECTION? THIS SHOWS YOU STAINING FOR IT AND PROTEIN TO CONTROL CELLS. WHEN YOU INFECT THE CELLS, YOU CAN SEE THAT IN THE CORE POSITIVE CELLS HERE, THIS IS SORT OF THE ENLARGED VIEW, THERE IS NDRG EXPRESSION PRETTY MUCH ALL GONE. SO BASICALLY AGAIN IT'S DOWN REGULATING, THE PARTICULAR CELLS INFECTED WITH HCV. AND THIS CAN BE SPECIFIC THERE, AND THEN NOW GOING BACK TO LIPID LIKE I TOLD YOU BEFORE. IT'S REGULATING LIPID DROPLET FORMATION. IF YOU LOOK AT THIS PARTICULAR STAINING WITH THE LIPID DROPLETS , IF YOU LOOK AT THE NORMAL CELLS, NDRG EXPRESSION IS CYTOPLASTIC. YOU HAVE CERTAIN LIPID DROPLETS. WHEN YOU KNOCK DOWN NDRG IN THOSE CELLS WHO HAVE MUCH MORE REDUCED NDRG, YOU CAN SEE THESE BIG LIPID DROPLET FORMATIONS THERE. I THINK IT'S PRETTY OBVIOUS. THIS SUGGESTS THAT NDRG IS REGULATING LIPID DROPLET FORM ATION IMPORTANT FOR HCV ASSEMBLY. THIS CAN BE QUANTIFIED SHOWING THAT IN IN THE NDRG KNOCK DOWN CELL YOU HAVE SIGNIFICANT IN CREASE IN LIPID DROPLETS, ALSO USING MICROARRAY EXPRESSION STUDY WOULD SHOW THAT MANY OF THESE LIPID GENIC PATHWAYS WITH PARTICULAR ALPHA, IT'S DIS REGULATED IN THE NDRJ SILENT CELLS. THIS BRINGS US BACK INTO -- WHAT WHAT'S ACTUALLY INVOLVED IN -- GOING BACK TO THE OLD MOLECULE M YC. IT'S UPREGULATED SHOWN HERE, LOOKING AT A TIME COURSE. ALSO VALIDATED BY USING WESTERN BLOT, AGAIN, IN THE NDRG1 INFECT ED CELLS. HCV INFECTED CELLS. WAS INCREASED IN MYC. THIS IS PROBABLY DUE TO IN DUCTION OF MYC BY HVC. WHAT DOES THAT HEENE? BACK TO THE WHOLE MAP, THAT VIRUS GETTING TO THE CELL, WANT TO SURVIVE. WHAT THE VIRUS DOES THROUGH THE BETA PATHWAY, I DON'T HAVE TO SHOW, UP REGULATE THE MYC, WHAT WE KNOW. THE UP REGULATION, THEN DOWN REGULATED MDRG SHOWN HERE. SO WHAT THIS PARTICULAR PATHWAY DOES, IT -- NDRG IS SPECIFIC TO BLOCK THE LIPID DROPLET PATHWAY, FUNCTION CELL. AND SO WHEN YOU DOWN-REGULATE YOU HAVE THE INCREASED LIPID DROPLETS, THAT'S WHAT THE VIRUS WANTS. ALSO, MYC, WHAT IT ALSO DOES, AS I MENTIONED, IT'S AN ONCOGENE. YOU CAN UPREGULATE MANY DIFFERENT CELL PRO LIVIVE JEEPS. TOGETHER, WITH UPREGULATED MYC, DOWN-REGULATED, YOU CAN IMAGINE THIS IS, AGAIN, PREMALIGNANT STAGE. IT'S LIKELY TO DEVELOP LIVER CANCER. I JUST WANT TO CONCLUDE THAT INFECTIONS, THAT MAPPING OF CRITICAL PATHWAY INTERACTION GEN RESTAURANT NOVEL INSIGHT INTO THE MECHANISMS. PREDISPOSES TO HCC DEVELOPMENT. AND THIS PHENOTYPE CAN BE INTEGRATED INTO THE GENIC LANDSCAPE OF ESTABLISHED HCC SUPPORTING THE FACT THAT FOR ETIOLOGY SUCH AS HCV, THERE IS UNIQUE GENETIC SIGNATURE AND PROGRAMMING LEADING TO MALIGNANT TRANSFORMATION. AND AGAIN, BACK TO THE MAJOR POINT, THAT HCC, A HETEROGENEOUS CANCER. EACH TYPE DEFINED BY ITS ETIOLOGY AND GENETIC LANDSCAPE. AND THEREFORE, IT'S ACTUALLY AN IDEAL CANDIDATE FOR PRECISION MEDICINE. WE KNOW THE GENETIC SIGNATURE, THAT'S HOW WE CAN TARGET THE TREATMENT REGARDING PREVENTION AND THERAPY. AND GETTING BACK TO THE WHOLE POINT THAT THE -- YOU CAN SEE THAT I'M JUST TRYING TO ILLUSTRATE THAT HCV INFECTION IS A WONDERFUL BIOLOGICAL MODEL SYSTEM TO LOOK AT VARIOUS BIOLOGY. YOU SEE THE UNANTICIPATED PATHWAY THAT HCV TAKE ADVANTAGE OF IT, ALTHOUGH IT'S TO ITS OWN ADVANTAGE, BUT WHAT IT DOES IS LEADING TO MANY DIFFERENT CONDITIONS THAT BASICALLY SET THE CELL TO A PREMALIGNANT CONDITIONS. AND I THINK YOU ALL KNOW WELL THAT -- HOW THE WHOLE FIELD OF ONCOLOGY EVOLVED, CAME ABOUT BECAUSE SOMEBODY BACK IN THE 19 th CENTURY NOTICED IN CHICKEN, WHEN THE INFECTED WITH SARCOMA VIRUS, THEY GET THESE TUMORS, THAT'S HOW THE TUMOR VIRUS BEING DISCOVERED iAND CLEARLY WHAT I'M TRYING TO SHOW HERE IS THAT BY STUDYING HCV, WE CAN GAIN MUCH GREATER UNDERSTAND ING OF THE BASIC MECHANISM OF TUMOR GENESIS. SO WITH, THAT I WANT TO STOP AND THEN SHOW -- RECOGNIZE THE PEOPLE WHO HAVE CONTRIBUTED TO THE WORK. AND THESE ARE THE PEOPLE I MENTIONED THEIR NAME DURING THE TALK. I WON'T GO ANY GREAT DETAIL. JUST BEEN A WONDERFUL OPPORTUNITY WORKING WITH THESE PEOPLE THAT CAN CONTRIBUTE TO ALL THESE DIFFERENT ASPECTS OF H CV INFECTION, WITH PARTICULAR INTEREST IN TERMS OF HOW THIS HC V CAUSES LIVER CANCER. THANK YOU VERY MUCH FOR YOUR TIME. [APPLAUSE] >> THANK YOU VERY MUCH. IT'S BRILLIANT. WE HAVE TIME FOR A FEW QUESTIONS AT THIS POINT. WE HAVE ALSO HAVE QUESTIONS AFTERWARDS. I WOULD ASK YOU TO PLEASE USE THE MICROPHONE BECAUSE THERE ARE A LOT OF PEOPLE ONLINE AND THEY CAN'T HEAR. THEY HEAR THE ANSWERS BUT NOT THE QUESTIONS. DO WE HAVE ANY QUESTIONS THAT SOMEONE WOULD LIKE? YES. >> SO YOU MENTIONED NASH AS A CAUSATIVE FACTOR. DOES NASH PRODUCE THE SAME KIND OF LIPID DROPLETS THAT ARE NEEDED BY THE VIRUS? OR SOME OTHER LIPID FORMATION? >> IF YOU LOOK AT THE HISTOLOGICAL FINDINGS OF HEPATITIS C AND NASH, SOMETIMES THE INADDITIONABLE. THEY ALL HAVE LIPID DROPLET FORM ATION, THEY HAVE SO-CALLED [INDISCERNIBLE]. SO IN A WAY, THAT -- THERE MAY BE SOME COMMONALITY IN TERMS OF HOW THEY CAUSE LIVER INJURY. CLEARLY FOR DIFFERENT REASON. I MEAN NASH CAN CAUSE INJURY AND POTENTIAL LIVER CANCER, REALLY THROUGH THIS SORT OF DISREGULAT ED LIPID METASTASES METABOLISM. AND THERE IS A LOT OF THINGS TO UNDERSTAND WHY THAT IS THE CASE. I THINK WHAT HCV DOES IS IT DOES THIS SORT OF -- IT'S A BYPRODUCT , NOT INTENDING TO DO, BUT IT DOES IT BECAUSE IT NEEDS IT FOR ITS SURVIVAL. BUT BY DOING THAT, CAUSING THESE SIMILAR TYPE OF PERTUBATIONS, I THINK THAT'S THE POINT I'M TRYING TO MAKE, THAT THE VIRUS DOESN'T DO THAT FOR SURVIVE. IT DOES IT BECAUSE THAT'S WHAT HAPPENS. >> SO JAKE, PRIMARY LIVER CANCER S OFTEN MULTI FOCAL. ALWAYS BEEN AN ARGUMENT WHETHER THESE ARE SEPARATE PRIMARIES, OR METASTASES, HAVE YOU HAD AN OPPORTUNITY TO EXAMINE THOSE DIFFERENT NODULES AND DO THEY SHOW A SIMILAR GENETIC PHENOTYPE >> WELL, I THINK A LOT OF PEOPLE DOING THAT, ACTUALLY AS I MENTIONED SOME OF THESE INVESTIGATORS, SPECIFICALLY USING GENOMIC TECHNOLOGY, TRANSCRIPTOME, WHOLE GENOME SEQUENCING. IF YOU LOOK AT THESE LESIONS, SEE HORTHY COME ABOUT. I'M CERTAINLY NOT SURPRISED THAT YOU COULD HAVE MULTIPLE TUMORS. I THINK PEOPLE HAVE SHOWN THAT, ESPECIALLY IN CEROTIC LIVER. AND IT'S NOT SURPRISING TO THINK THAT THE VIRUS IS REALLY CAUSING VARIOUS DIFFERENT GENETIC ALT ERATION AND DIFFERENT CELLS. SO REALLY DEPENDS ON THE TYPE OF DAMAGE AND GENETIC ALTERATION. THEY COULD COME OUT AROUND THE SAME TIME OR SOME ARE LATER THAN OTHERS. I CAN THIS IS A LOT OFF -- NOT JUST HEPATITIS C. IF YOU LOOK AT OTHER DISEASES, THERE ARE A LOT OF THEORIES THAT GO THROUGH WHY IT'S LIKELY YOU SEE MULTI FOCUS LIVER CANCER. >> OKAY. I THINK WE'LL MOVE ON. WE'LL HAVE TIME FOR QUESTIONS AT THE END. THANK YOU VERY MUCH, JAKE, THAT WAS EXTRAORDINARY. DR. JOHNSON. >> THANK YOU EVERYBODY. THANK YOU FOR THAT WONDERFUL INTRODUCTION. I AM SORT OF A SECOND GENERATION TRANSPLANTER. TOM, MY MENTOR, HIS SECOND FELLOW ALONG WITH BUZZ SHAH IN PITTSBURGH. INDIVIDUALS WOULD SPEND ABOUT 6 MONTHS WITH TOM, AND THEN DO 20 OR 30 TRANSPLANTS AND START THEIR OWN TRANSPLANT PROGRAM. WHICH WAS DONE IN BOSTON BY ROGER JENKINS. MY ASPIRATION WAS TO DO THE SAME THING, SO I'M KIND OF THE LAST GENERATION WHO ACTUALLY FINISHED THEIR FELLOWSHIP AND WENT RIGHT INTO STARTING THEIR OWN TRANSPLANT PROGRAM, WHICH NOW DAYS, UNHEARD OF. ACTUALLY, YOU WOULD NEVER BE ABLE TO DO THAT GIVEN THE INTEREST AND THE AMOUNT OF RESOURCES IT TAKES TO RUN ONE OF THESE PROGRAMS. BUT I'M GOING TO FOCUS MOST OF MY TALK ON THE TREATMENT ASPECT -- WITH AN EMPHASIS ON LIVER TRANSPLANTATION. WE'LL TALK ABOUT SURGICAL RE SECTION AND ABLATIVE THERAPIES SO I WON'T BELABOR THIS POINT. BUT HCC IS THE MOST COMMON PRIMARY, NEOPLASM OF THE LIVER. MOST CANCERS THAT OCCUR IN THE LIVER ARE METASTATIC IN NATURE. AS FAR AS PRIMARY LIVER CANCERS, HCC IS THE MOST COMMON. AS JAKE SHOWED, IT IS THE SECOND MOST FREQUENT CAUSE OF CANCER DEATH WORLDWIDE. IN THE INCIDENCE IS INCREASING, ESTIMATED ABOUT 21,000 CASES IN THE U.S. IN 2008, ESTIMATED TO BE ABOUT 27,000 IN 2020. AND ONE OF THE FASTEST GROWING DEATH RATES IN THE U.S. SO ONE OF THE THINGS THAT'S BEEN A BENEFIT OF MICROSOFT OFFICE PRODUCTION THAT YOU ALL PURCHASE TO RUN YOUR POWER POINTS AND OTHER THINGS, IS THAT THE BILL AND MELINDA GATES FOUNDATION THAT IS PLEDGED OVER $10 BILLION TO VACCINE NATION AND PRIMARILY IN ARABIA ASIA AND AFRICA. 5% OF THE WORLDWIDE POPULATION IS INFECTED WITH HBV, A VERY HIGH INCIDENCE IN ASIA AND AFRICA. IT'S ESTIMATED THAT THE ASHEN NEO NATAL VACCINE PROGRAM WILL REDUCE THE INCIDENCE BY 75-80%. SO CLEARLY, SOMETHING THAT IS VERY WORTHWHILE FOR THAT FOUND ATION TO DO. AS WE MENTIONED, TODAY, HEPATITIS C IN THE UNITED STATES HAS BEEN THE AMERICA DRIVER OF H CC WITH OVER 4 MILLION INDIVIDUALS INFECTED IN THE U.S. CHRONIC INFECTION OCCURS IN 70- 80% OF THE INDIVIDUALS. ABOUT 18% OF THE POPULATION IS INCH EGYPT, AS COMPARED TO 1.8% HERE IN THE U.S. AND WITH THE ADVENT OF DIRECT ACTING ANTIVIRALS, CURATIVE TREATMENTS FOR HEPATITIS C, IT IS -- WE NOW SEE THAT THERE IS ABOUT A 30% REDUCTION IN CIRRHOSIS SECONDARY TO ACC FROM HEPATITIS C VIRUS ON THE TRANSPLANT WAITING LIST. NASH IS NOW STARTING TO OVERTAKE HEPATITIS C AS THE MOST COMMON INDICATION THAT DRIVES HCC ON THE LIVER TRANSPLANT LIST. NAFLD/NASH IS THE MOST PREVALENT LIVER DISEASE IN U.S. SIXTY% OVER THE AGE OF 50 WILL HAVE THAT. AND THE NASH RELATED HCC LETTER TRANSPLANT PATIENTS ON THE WAITING LIST HAS INCREASED BY 4 TIMES FROM 2002-2012. SO CLEARLY, A BIG PLAYER AS IT RELATES TO THE NEED FOR LIVER TRANSPLANTATION. SO HCC IS AN UNUSUAL CANCER BECAUSE IT'S ONE OF THE FEW CANCERS THAT BASICALLY OCCURS IN A SETTING OF 2 DISEASES. YOU HAVE 2 SIMULTANEOUS DISEASES GOING ON IN MOST PATIENTS WHEREAS YOU HAVE CIRRHOSIS AND SCARRING IN THE LIVER ON ONE HAND, AND YOU HAVE THE CANCER ON THE OTHER HAND. WHEREAS MOST CANCERS FORM IN NORMAL TISSUE. AND SO THE MANAGEMENT, BECAUSE OF THE UNDERLYING DISEASED ORGAN , BECOMES COMPLEX. BECAUSE YOU HAVE TO UNDERSTAND THE STAGE OF THE TUMOR BUT ALSO THE STAGE. CIRRHOSIS TO PAIR THE RIGHT TREATMENT WITH THE RIGHT PATIENT. IN THE SETTING OF ADVANCED DISEASE, THE SURVIVAL FROM ACC IS VERY BUSINESSMAL, ABOUT -- ABYSMAL, TEN% IN FIVE YEARS. WITH PATIENTS WITH LIMITED TUMOR BURDEN, A CURATIVE TREATMENTS CAN OCCUR. AND AS WAS MENTIONED ABOUT THE MULTI FOCAL NATURE OF HCC, CERTAINLY HAS A PREDILECTION FOR MICROAND MICROVASCULAR INFASHION WHICH TENDS TO PORTEND TO A POOR PROGNOSIS. WITH THAT WE'LL HAVE OUR FIRST QUIZ OF THE DAY. YOU DIDN'T KNOW YOU WERE GOING TO BE TESTED BUT YOU ARE. AND SO THE QUESTION IS WHICH ARE AT RISK POPULATIONS FOR DEVELOPING HEPATITIS CARCINOMA. A, CHRONIC HEPATITIS C. BE, CIRRHOSIS DUE TO HEPATITIS B C, HEPATITIS B CARRIERS WITH FAMILY HISTORY OF HCC. D, HEPATITIS B CARRIERS WHO ARE ASIAN MALES, OVER THE AGE OF 40. E IS AND AND B. IF ALL THE ONE OF. WHO IS IN FAVOR OF A? WHO IS IN FAVOR OF B? AGAIN, NO ONE. C? NO TAKERS. D? NO TAKERS. E? NO TAKES. F. ALL RIGHT. WE GOT A SMART CREW HERE. THIS IS -- I'M GOING TO BE EMBARRASSED. YOU KNOW MORE THAN I DO. BUT THIS IS A SLIDE THAT YOU ALL -- YOU'RE ALL CORRECT. NOT ONLY DO PATIENTS WHO HAVE THE ACTIVE VIRUS, BUT CARRIERS OF THE DISEASE AS WELL, PARTICULARLY MALES WHO ARE ASIAN AND FEMALES, HAVE A HIGHER PREDILECTION. SO ANYONE WITH A FAMILY HISTORY OF ACC, ALSO A CARRIER AS WELL. SO IN TERMS OF THE OPTIONS FOR TREATMENT, THEY INCLUDE SEVERAL TECHNIQUES. CERTAINLY SURGICAL RESECTION STILL IS A MAIN STAY FOR TREATMENT MOOCH PARTICULARLY IN THE EASTERN COUNTRIES, EVEN IN THE U.S. AS WELL. TRANSPLANTATION AS YOU KNOW WE'LL TALK ABOUT. THEN THERE ARE MULTITUDE OF ABLATIVE TECHNIQUES. ALSO TOUCH ON A FEW OF THESE AS WE GO THROUGH THEM. AND LASTLY, AS JAKE MENTIONED, SORAFENIB SORAFENIB IS A MULTI FOCAL KINASE INHIBITOR WHICH PLAYS A ROLE FOR THOSE WITH ADVANCED DISEASE. AND THIS IS -- WOULD BE A TYPICAL PICTURE OF SOMEONE WHO PRESENTS WITH HEPATOCELLULAR CARCINOMA. FIFTY-FOUR-YEAR OLD AFRICAN MALE AFP WAS DROWN, 200. THEN HE HAD THIS MRI. AND ON THE MRI, YOU CAN SEE THE ARROWS POINTING TO THE ARTERIAL PHASE HYPER VASCULARITY WITH WASHOUT DURING THE PORTAL VENOUS PHASE. DELAYED PSEUDO CAPSULE ENHANCE MENT. FOR SOMEONE LIKE THIS, THE QUESTION IS, WHAT WOULD BE THE BEST TREATMENT AVAILABLE? IF YOU SAY, WELL, HE'S GOT A SINGLE MASS, AND SO WHY YOU DON'T TAKE IT OUT, THAT WOULD BE ONE CONSIDERATION. YOU HAVE TO SEE THAT THAT MASS IS NOT REALLY ON THE PERIPHERY. IT'S NEAR THE CENTER OF THAT RIGHT LOBBY, SO YOU'D HAVE TO DO A RIGHT LOW BECKMY, LEAVING THE PATIENT LEFT WITH 35 OR 40% OF THEIR LIVER VOLUME. IT MAY NOT BE ENOUGH FOR THAT PERSON TO SURVIVE ON. THESE ARE SOME OF THE CONSIDERATIONS IN ADDITION TO THE SEAR RHESUS OR NO CIRRHOSIS. THE UNDER LYING CHILD'S CLASS, WHICH IS A PREDICTOR. DEVISED TO BE A PREDICTOR OF SURVIVAL AFTER PORTAL CABLE SHUNTS IN THE 60S. AS YOU GO FROM A, B, C, THE WORSTer WORSENING OF THE UNDER LYING CIRRHOSIS. YOU HAVE TO CONSIDER THE TUMOR SIZE, NUMBER AND LOCATION. ONE OF THE THINGS THAT'S VERY IMPORTANT, PARTICULARLY IN PATIENTS WHO HAVE EARLY CIRRHOSIS, WHO HAVE A SOLID SINGLE LESION AND YOU WANT TO RE SECT THEM, DETERMINE WHETHER OR NOT THERE IS ANY PRESENCE OF HYPER PORTAL TENSION OR NOT. LASTLY, TUMOR BIOLOGY. PROBABLY THE MOST IMPORTANT THINGS. WITH FOLKS LIKE JAKE, WE WILL LEARN MORE ABOUT THAT IN THE FUTURE. RIGHT NOW WE DON'T KNOW A LOT FROM THE STANDPOINT OTHER THAN GRADUATION, WHAT REALLY ARE -- DRIVES AGGRESSIVE TUMOR BEHAVIOR THIS IS THE -- THIS COMBINES THE STAGE OF THE CANCER AS WELL AS THE UNDERLYING CONDITION OF THE LIVER. SO AS THIS -- FOR THE PURPOSES OF OUR DISCUSSION, WILL FOCUS ON THE EARLY STAGE CANCERS. AND SO THESE WOULD BE CANCERS THAT EITHER HAVE A SINGLE NODULE THAT ARE LESS THAN FIVE CENTIMETERS IN SIZE AND DIAMETER , OR UP TO 3 NODULES, WHICH EACH LESS THAN 3 CENTIMETERS. SO ONE OF THE MOST COMMONLY USED TREATMENTS FOR HCC, ADVANCED LOCAL REGIONAL ACC AS WELL AS A BRIDGE TO TRANSPLANT, THE USE OF TRANSARTERIAL CHEMO EMBOLIZATION IN THIS TECHNIQUE, THE LIVER HAS A DUAL BLOOD SUPPLY, BOTH PORTAL VENOUS IN-FLOW AND ALSO CARRYING BLOOD FROM THE MESENTERY SYSTEM FROM THE INTESTINES, ALSO HEPATIC ARTERIAL FLOW, AS WELL. THE TUMORS ARE PROFUSED BY THE ARTELLIER SYSTEM. AS OPPOSED TO HE PATCYTES. YOU CAN CATHS ARE AND FINDING THE FEEDING VESSELS TO THE TUMOR EMBOW LIES THEM. PRIOR TO THE EMBOLIZATION, THE CHEMO THERAPEUTIC AGENTS CAN BE INFUSED AND THEY CAN LEAD TO DE STRUCTION OF THE TUMOR. THERE IS SOME CONTRAINDICATIONS, CERTAINLY PATIENTS THAT HAVE DE COMP COMP COMPENSATING CIRRHOSIS DON'T DO WELL. PATIENTS WITH VERY LARGE TUMORS AND A PORTAL VAIN OCCLUSION BECAUSE OF THE CANCER ALSO DON'T DO WELL. YOU'VE ELIMINATED THE DUAL BLOOD SUPPLY, IF THE PORTAL VAIN HAS BEEN OCCLUDED. THIS IS A STUDY, RANDOMIZED -- VERY VIEW RANDOMIZED STUDIES OUT THERE IN SURGICAL PROCEDURES. BUT THIS IS ARAMIZED TRIAL -- RANDOMIZED TRIAL PUBLISHED IN LANCET IN PATIENTS WITH EARLY CIRRHOSIS. THEY WERE USING OVERALL SURVIVAL AS THE PRIMARY ENDPOINT. THEY HAD 112 PATIENTS. THEY EXPIRED CHEMO EMBOLIZATION VERSES SIMPLEMATIC CARE. THE OVERALL SURVIVAL AT ONE YEAR AND TWO YEARS FAVORED CHEMO EMBOLIZATION. IT CERTAINLY PLAYS A ROLE IN PATIENTS WHO HAVE ADVANCED DISEASE, BUT IT ALSO PLAYS A ROLE IN PATIENTS WHO ARE BRIDG ING OR WAITING FOR A TRANSPLANT ORGAN. A MORE RECENT TREATMENT THAT'S COME ON BOARD IS UTILIZING TRANS ARTERIAL RADIO EMBOLIZATION THIS IS ANOTHER SECURE NEEK OF A CATH -- TECHNIQUE OF CATHETER DELIVERY OF MICROSPHERES COATED, THAT THE LIVER LOW EMITTING RADIATION TO THE TUMOR. AND IN THIS INSTANCE, FOR SMALL TUMORS, ABOUT 3 CENTIMETERS OR LESS YOU CAN ACHIEVE ABOUT 90% TUMOR NEURO-INPUT CROSSES. THE ADVANTAGE OF RADIO EMBOW PUBLICATION, IT CAN USED EVEN IN PORTAL VAIN THROMBOSIS. YOU DON'T OCCLUDE THE VESSELS BY INJECTING THE MICROSPHERES. SO THAT IT CAN -- IT HAS A MUCH MORE FAVORABLE CONDITION FOR BROADER NUMBER OF PATIENTS. HOWEVER, THE DISADVANTAGE, YOU DO NEED A PRETREATMENT ARTERIO GRAM TO RULE OUT ARTERIAL PORTAL SHUNTING THAT OCCURS, SO THAT YOU DON'T HAVE UNINTENDED RADIATION TARGETS, PARTICULARLY TO THE LUNGS AND TO THE SYSTEMATIC SYSTEM HERE IS A RECENT RANDOMIZED TRIAL COMPARING RADIO EMBOW LIBRARIANIDATION IS [INDISCERNIBLE] 90 TO CHEMO EMBOLIZATIONS IN PATIENTS WITH H CC AWAITING TRANSPLANTATION. THIS WAS JUST PUBLISHED IN 2016, THE LEAD AUTHOR IS OUT OF NORTHWESTERN. IT WAS IN PATIENTS WITH EARLY STAGE CIRRHOSIS, AOB. FORTY-FIVE PATIENTS IN THE TRIAL THAT WERE RANDOMIZED TO RADIO EM BOW LIBRARIANIDATION OR TACE. THE PRIMARY ENDPOINT HERE WAS TIME TO PROGRESSION. SO IT WAS NOT OVERALL SURVIVAL, BUT THE TIME THAT THE TUMORS STARTED TO GROW AGAIN. IN THEIR ANALYSIS THEY SHOWED TIME TO PROGRESSION WAS 26 MONTHS COMPARED TO 6 MONTHS FOR CHEMO. THE OVERALL SURVIVAL, WHEN CENSURED FOR THE TRANSPLANT, WAS NO SIGNIFICANT DIFFERENCE. ON THE BASIS OF THIS, MANY INDIVIDUAL RADIOLOGY PROGRAMS AND ALSO TRANSPLANT PROGRAMS HAVE CHOSEN TO USE RADIO EMBOLIZATION. THE ONE THING NOT DONE IS TO DEMONSTRATE THE COST EFFECTIVE NESS OF THE THERAPY AS IT RELATES TO COMPARATIVE TO CHEMO EMBOLIZATION. SO THAT AS A RESULT, THE PREMIERE TRIAL, SAFE WITH PATIENTS WITH PORTAL VAIN THROMBOSIS. BUT THE CAVIOUS, EXCESSIVE RADIATION CAN PRODUCE SIDE EFFECTS IN PATIENTS TO NON TARGET ORGANS WHICH IS THE DOWN- SIDE OF RADIO EMBOLIZATION. SO LET'S TALK ABOUT LIVER TRANS PLANTATION. CERTAINLY, LIVER TRANSPLANTATION HAS THE MOST DURABLE OUTCOME WITH THE LOWEST RECURRENCE, THE ONLY TREATMENT THAT TAKES CARE OF BOTH THE CANCER AS WELL AS THE UNDERLYING CIRRHOSIS. SO YOU DEAL WITH BOTH PROBLEMS. HOWEVER, ORGAN AVAILABILITY REMAINS A CHALLENGE, WE DON'T HAVE ORGANS AVAILABLE ON THE SHELF FOR EVERYBODY THAT NEEDS THEM. MOST PATIENTS HAVE TO BE ON A WAITING LIST. HOW YOU ALLOCATE THE ORGANS STILL REMAINS AN ISSUE. THERE ARE CERTAINLY -- THERE IS A PRESSURE FOR EARLY STAGE PATIENTS WITH A ON THE WAITING LIST VERSES THON WITH NON MALIGNANT INDICATIONS. THE OTHER PROBLEM WITH USING TRANSPLANTATION IS THAT THE OUTCOMES IN PATIENTS WHO HAVE VASCULAR INVASION, WHICH OFTEN TIMES YOU CAN'T TELL UNTIL YOU HAVE THE EX-PLANTED LIVER. YOU LOOK MICROSCOPICALLY AT IT, IS QUITE DIFFERENT THAN THOSE PATIENTS THAT DON'T HAVE VASCULAR INVASION. SO RIGHT NOW, THE ONLY THANK WE HAVE IS A -- THING WE HAVE IS A SURROGATE TORE VASCULAR INVASION , IS DETERMINING THE SIZE AND NUMBER OF LESIONS IN THE LIVER TO ESTIMATE WHICH TUMORS MAY OR MAY NOT HAVE INVASION AND THERE ARE, WOULD BENEFIT MORE FROM TRANSPLANTATION. SO BACK IN PROBABLY THE -- AROUND 19 -- WELL, PAPER WAS PUBLISHED IN 1996. BUT 1996, TRAN MANTATION WAS REALLY NOT A VIABLE OPTION FOR HEPATITIS CARCINOMA. NO ONE HAD FIGURED OUT HOW TO SELECT PATIENTS WELL. THERE WERE FEW ISOLATED INCIDENTS. A LOT OF THOSE PATIENTS WOULD RECUR. WITH A SCARCE RESOURCE AS AN ORGAN, TRANSPLANTATION FOR CARP WAS NOT REALLY EMPLOYED. HOWEVER, IN THIS SENTINEL PAPER BY THE GROUP FROM ITALY, PUBLISH ED IN THE NEW ENGLAND JOURNAL, SHOWED THAT IF YOU SELECTED OUT PATIENTS, THIS WAS CALLED THE MIDLINE CRITERIA, STILL CALLED THAT, WITH THE SINGLE TUMOR, LESS THAN FIVE CENTIMETERS OR UP TO THREE TUMOR S WITH EACH LESS THAN THREE CENTIMETERS, NO GROSS VASCULAR INVOLVEMENT, NO OBVIOUS DISTANCE METASTASES, YOU COULD TRANSPLANT THOSE PATIENTS AND HAVE A VERY GOOD SURVIVAL. SURVIVAL AT 75% OF FOUR YEARS WITH RECURRENCE RATES OF THEN 8% THE GROUP FROM UCFS LATER ON IN 2007 TOOK IT ONE STEP FURTHER, SAID THAT IF YOU SELECT PATIENTS OUT NOW WITH TUMORS UP TO 6 AND A HALF CENTMETERS, AND TUMOR WHEN YOU HAVE THE ADDITIVE UP TO 3 TUMORS LESS THAN 8-CENTIMETERS , THOSE PATIENTS ALSO CAN BE TRANSPLANTED. THEY DEMONSTRATED AN 82% SURVIVAL AT FIVE YEARS FOLLOWING THEIR TRANSPLANT WITH ONLY A 9% RECURRENCE RATE. SO CLEARLY, THERE IS MORE TO IT THAN JUST SIZE AND NUMBER. BUT AS I MENTIONED, I THINK MOST OF US IN THE FIELD BELIEVE THAT THOSE ENTITIES ARE REALLY JUST SURROGATES FOR WHAT'S MOST IMPORTANT ABOUT THE TUMOR BIOLOGY. SO WHY NOT JUST TRANSPLANT EVERYBODY? IT TAKES CARE OF THE SEAR ROSE, TAKES CARE OF EARLY CANCER. WELL, AT IT TURNS OUT, THERE IS A WAITING LIST. THIS SLIDE SHOWS YOU THAT AS OF 2010, THERE WERE ABOUT 110,000 PATIENTS WAITING ON THE ORGAN TRAN PLANT LIST IN THE UNITED STATES. 24,000 PATIENTS WERE TRANSPLANT ED. SO THERE IS A HUGE GAP BETWEEN THE TWO. AND DECIDING HOW YOU ALLOCATE THOSE ORGANS BECOMES VERY IMPORTANT. ON TOP OF THAT, THERE IS A WAITING LIST, IN PATIENTS WHO HAVE CANCER, HAVE TO SIT ON A WAITING LIST. SOME OF THOSE PATIENTS WILL PROGRESS AND TROP OUT OF THE WAITING LIST BECAUSE THE TUMOR HAS BECOME ADVANCED OR THEY DIE ON THE WAITING LIST. IF YOU DO AN INTENT TO TREAT ANALYSIS, LIVER TRANSPLANTATION DOESN'T HAVE THE SAME ADVANTAGE AS SOME OF THE MORE IMMEDIATE PROCEDURES THAT ONE CAN DO NEXT WEEK WHEN YOU'RE TALKING TO A PATIENT AS OPPOSED TO 6 MONTHS OR A YEAR DOWN THE ROAD. IN ADDITION, THERE IS A LIFE LONG IMMUNOSUPPRESSION THAT PATIENTS HAVE TO TAKE IN ORDER TO KEEP THEIR ORGANS FROM HAVING ANY EVIDENCE OF REJECTION. SO FROM THE STANDPOINT OF THE ALLOCATION SYSTEM AND HOW WE ALLOCATE ORGANS IN THE UNITED STATES, IN LIVER TRANSPLANTATION , THAT PRIORITY SYSTEM IS BASED ON WHAT'S CALLED A MELD SCORE. THAT SCORE IS BASED ON NUMBER BASED ON SEAR UP BILIRUBIN, CREATININE AND INR. THAT NUMBER IS GENERATED BETWEEN 6 AND 40. IT COMES OUT. AND THE PATIENTS WITH THE HIGH EST NUMBER OR SICKEST ORGAN HAS THE HIGHEST PRIORITY. IN THE UNITED STATES, ALL OF THESE SMALL SERVICE AREAS, SOME OF WHICH CONFINE TO AN ENTIRE STATE, SOME WHICH ARE JUST IN A REGION OF A STATE. BUT EACH REGION -- EACH SERVICE AREA SERVICES A WAITING LIST OF PATIENTS THAT THEY HAVE IN THEIR OWN SERVICE AREA FIRST BEFORE GOING TO BROADER SHARING. AND SO ONE OF THE THINGS THAT WAS DONE IS TO TRY TO CREATE A SYSTEM THAT ALLOWS SOME PRIORITY FOR PATIENTS WHO HAVE HCC MANY OF THESE DON'T HAVE HIGH MELD SCORES. THEY WOULD NEVER BE TRANSPLANTED SO WHAT WAS DONE IN 2000, CREATE WHAT'S CALLED A MELD ELEVATOR. SO PATIENTS WITH HCC THAT FIT WITHIN THAT MALIGNED CRITERIA WOULD BE GIVEN 22 POINTS. EACH 3 MONTHS THAT THEY STAYED ON THE LIST, AN ADDITIONAL 3 POINTS WOULD BE GIVEN. AND SO THAT WAS A WAY IN WHICH I COULD HELP PRIORITIZE AND GET THESE PATIENTS TRANSPLANTED IN A QUICK FASHION. THE UNINTENDED CONSEQUENCES OF THAT WAS THAT HCC PATIENTS BEGAN TO DOMINATE THE LIVER TRANSPLANT LIST, AND THE WAIT LIST MORTALITY AND DROPOUT, WHEN YOU HAD HC CC, WAS FAR LEST THAN IT WAS FOR PATIENTS WHO HAD NON MALIGNANT DISEASE THAT HAD WORSE CIRRHOSIS. AS YOU CAN SEE HERE, AT THIS POINT, HALF THE PATIENTS ON THE WAITING LIST WERE PATIENTS WHO HAD HEPATITIS HEPATOCELLULAR HEPATOCELLULAR CARCINOMA. IN 2015, JUST A YEAR-AND-A-HALF AGO, A NEW POLICY CAME INTO PLAY WHICH WAS AN HCC DELAY POLICY, WHICH SAID THAT IF YOU LISTED SOMEBODY WITH CANCER ON THE WAITING LIST, THERE WAS A 6 MONTHS DELAY BEFORE THAT PATIENT RECEIVED ANY POINTS. THEY COULD GO ON THE LIST AT THEIR NATURA MELD SCORE. BEFORE THEY GOT THE POINTS THEY HAD TO WAIT 6 MONTHS. AND THE IDEA THERE WAS TO DE CREASE THE NUMBER OF TRAN PLANTS IN REGIONS WHERE TRANSPLANTS OCCURRED AT LESS THAN 28 POINTS. IDENTIFY PATIENTS WITH AGGRESSIVE TUMOR BIOLOGY. SO THAT IN A WAY, IT WAS A SELECTION PROCESS. IF A PATIENT WENT ON THE LIST, AGGRESSIVE TUMOR BIOLOGY, AND THEY -- IT GREW ON THE LIST THEY WOULD BE ABLE TO DROP OFF AND NOT BE ELIGIBLE. THEY WOULD NOT RECEIVE THE POINTS UNTIL THEY WERE ON THE LIST FOR 6 MONTHS. THEY ALSO CAPPED THE AMOUNT OF POINTS THAT THEY GOT BY -- AT 34. EACH 3 MONTHS YOU STILL GET AN ADDITIONAL 3 POINTS. ONCE YOU GET UP UP TO 4 , YOU STOP. THE -- 34, THEY STOP. THERE IS A MANDATORY OF SHARING FOR ANY ORGAN IN A LARGER AREA THAT HAS MORE THAN 35 POINTS. I KNOW THAT'S VERY CONFUSE. BUT YOU CAN UNDERSTAND THE DIFFICULTY OF TRYING TO CREATE A SYSTEM THAT'S FAIR, BUT AT THE SAME TIME, USES THE BEST UTILIZATION OF THE ORGANS. EVEN WITH THIS SYSTEM THERE ARE ISSUES NOT RESOLVED. THAT IS, DO WE ASSIGN THE SAME M ELD FOR ALL PATIENTS WITH ACC REGARDLESS OF THEIR NATURAL MELD THAT IS TO SAY IF YOU HAVE CANCEROMA, YOU HAVE EARLY SCLEROSIS, SHOULD YOU GET THE SAME POINTS AS SOMEBODY WITH ADVANCED CIRRHOSIS? AS THE SYSTEM STANDS NOW, YOU DO IT MAY BE BETTER TO INCLUDE NATURAL MELD, TUMOR BURDEN AND OTHER MARKERS TO BETTER IDENTIFY TRANSPLANT RELATED SURVIVAL BENEFIT. SO I'M GOING TO SHOW YOU A FEW SLIDES HOW THE ACTUAL OPERATION IS DONE. AND IN THIS SLIDE, PROBABLY DATES BACK TO THE TIME OF TOM, WHAT IT SHOWS YOU IS THAT THE LIVER HAS BEEN EXPLANTED OR RE MOVED FROM THE BODY CAVITY. AND BECAUSE YOU HAVE TO DISRUPT THE BLOOD FLOW THROUGH THROUGH THE VENA CAVA, THE MAIN VESSEL CARRYING BLOOD BACK TO THE HEART , TYPICALLY IN THE OLD DAYS A BYPASS MACHINE WAS USED. YOU PUT A CANNULA IN A FEMORAL AND PORTAL VAIN. YOU HAVE A ROLLER POINT THAT RETURNED BLOOD INTO THE RIGHT ATRIUM. AND WHILE THAT ROLLER PUMP WAS GOING ON, THE LIVER WOULD BE BROUGHT UP TO THE TABLE. THIS IS THE NEW ORGAN REMOVED FROM A DONOR AND SEASON INTO PLACE. THIS -- SOWN INTO PLACE. THIS WOULD BE THE OLD CEROTIC LIVER. THIS WOULD BE THE NEW RIVER THAT WOULD BE PUT INTO PLACE. SO SOME OF THE OTHER ISSUES RELATED TO TRANSPLANTATION THAT ARE NOT FREE IS THE FACT THAT PATIENTS HAVE TO BE ON IMMUNO SUPPRESSION. THERE ARE A NUMBER OF LONG TERM COMPLICATIONS RELIGHTED TO IMMUNOSUPPRESSION. CERTAINLY THE MOST SIGNIFICANT ARE THE SUSCEPTIBILITY TO OPPORTUNISTIC INFECTIONS, AS WELL AS TOMBS RELATED TO IMMUNO SUPPRESSION. SO I'M GOING TO TALK A LITTLE BIT ABOUT TWO OTHER TECHNIQUES THAT ARE CURRENTLY USED TO HELP MANAGE PATIENTS WITH HCC ONE IS RADIO FREQUENCY ABLATION. YOU CAN THINK OF THAT AS MICROWAVE TREATMENT, ALTHOUGH MICROWAVE ABLATION IS A LITTLE BIT DIFFERENT. WITH YOU BASICALLY, YOU PLACE IN PROBES. THIS IS A TYPICAL RFA PROBE. IT GOES IN AS A NEEDLE. THEN IT HAS THESETINES THAT YOU PUSH OUT, OPEN UP LIKE THE SPINE S OF AN UMBRELLA. YOU CAN SEE OTHER HERE ONCE -- YOU CAN USE ULTRASOUND. YOU PUT IT IN THE TUMOR, THEN YOU CONNECT IT TO A GENERATOR, THAT, THEN, PRODUCES -- USUALLY HEATS UP TO 80 TO 110 DEGREES CELSIUS, WHICH CAUSES DENAR ERATION OF THE CRITICAL MEMBRANES AND NEEK ROSIS GENERAL LY UP TO ABOUT 3- CENTIMETERS IN SIZE. THE TROUBLE WITH IT IS THAT IN DIFFERENT TO REACH SEGMENTS ESPECIALLY, WHEN YOU'RE DOING IT PURCHASE CUTANEOUSLY, IT'S HARD TO POSITION INTO AREAS THAT PARTICULARLY AT THE DOME OR THE TOP OF THE LIVER. THIS WAS A STUDY SHOWING OUTCOME , ANOTHER RANDOMIZED TRIAL SHOWING OUTCOME WHEN YOU COMBINE CHEMO EMBOLIZATION AND RADIO FREQUENCY ABLATION VERSES RESECTION FOR PATIENTS THAT HAVE EARLY CANCERS IN EARLY CIRRHOSIS LOOKED AT 200 PATIENTS. THEIR PRIMARY ENDPOINT WAS OVERNIGHT ALL SURVIVAL WITH A SECONDARY ENDPOINT OF DISEASE- FREE SURVIVAL. FROM THE OVERALL SURVIVAL, AT 3 YEARS AFTER THEIR TRANSPLANT, YOU CAN SEE THAT THERE IS AN 83% SURVIVAL IN PATIENTS WHO UNDER WENT RESECTION. VERSES THOSE THAT UNDER-WENT COMBINED RADIO FREQUENCY OBLATION. AT FIVE YEARS, AGAIN, SURVIVAL ADVANTAGE USING SURGICAL RE SECTION. SAME THING HOLDS TRUE WITH WHEN LOOKING AT DISEASE-FREE SURVIVAL SO I'M NOT GOING THROUGH ALL THESE. BY LIVER RESECTION IS THE LAST TYPE OF TREATMENT THAT WE'LL TALK ABOUT. AND LIVER RESECTION CAN BE CUR ATIVE IN PATIENTS WHO HAVE HC C. THE -- AS I MENTIONED, THE BIG PROBLEM WITH LURCH ESECTION, THAT DEPENDS ON HOW MUCH RECOMMEND MANT LIVER YOU'RE LEAVING BEHIND, PARTICULARLY WITH SOMEBODY THAT HAS A CEROTIC LIVER. THE ONLY DISEASE THAT CAUSES HCC TO OCCUR WITHOUT CIRRHOSIS IS HEPATITIS B, NOT AS COMMON IN THE U.S. ONLY ABOUT 20% HAVE PATIENTS ARE ELIGIBLE DUE TO [INDISCERNIBLE] AS WELL AS THE PRESENCE OF ADANCED CIRRHOSIS. WHEN YOU DO LIVER RESECTIONS, YOU HAVE TO UNDERSTAND THAT THERE IS A COSTUME LAIVE RECURRENCE RATE, ABOUT TEN% PER YEAR. SO WHEN YOU RESECT SOMEBODY, RE MOVE THEIR TUMOR, YOU CAN EXPECT ABOUT 50% RECURRENCE RATE AT 5 YEARS. SO MANY -- PARTICULARLY EUROPEAN CUPS BELIEVE THAT YOU HAVE A RESECTABLE LESION, BEST TO DO RE SECTION FIRST, THEN MONITOR PATIENTS FOR RECURRENCE. IF THEY RECUR, THEN USE TRANSPLANT AS A SECOND LINE THERAPY AS OPPOSED TO A FIRST LINE THERAPY THAT OFTEN TIMES IS USED HERE IN THE U.S. SO SURGICAL RESECTION IS BEST SUITED FOR PATIENTS WITH HEPATOCELLULAR CANCER WITH A SINGLE CARP CANCER. THERE IS A FOYER OVERALL SURVIVAL OF AROUND 60 TO 70%. AS I SAID, THE -- WHICH IS SIMILAR TO WHAT YOU SEE IN SOME OF THE TRANSPLANT SERIES, HOWEVER, THE DIFFERENCES IN THE DISEASE-FREE SURVIVAL WHICH TRAN TRANSPLANTATION WOULD BE MUCH BETTER. SO I'M GOING TO CONCLUDE WITH THAT AS AN END, BUT THE POINTS THAT I WOULD LIKE TO RE- EMPHASIZE IS THAT OF ALL THE TREATMENTS, LIVER TRANS PLANTATION PROVIDES THE MEDAL OF SCIENCE DURABLE OUTCOME S -- PROVIDES THE MOST DURABLE OUTCOMES. IF YOU USE INTENT TO TREAT ANALYSIS, SOME OF THE PATIENTS YOU WANT TO TRANSPLANT WILL END HAVE PROGRESSING, FALL OFF THE WAITING LIST OR DIE BECAUSE YOU HAVE TO WAIT THAT PERIOD OF TIME SELECTIVE PATIENTS WITH VERY EARLY OR EARLY STAGE TUMORS WITH NORMAL LIVER FUNCTION CAN BE CANDIDATES FOR RESECTION OR ABLATIVE THERAPIES. THE OVERALL SURVIVAL AND DISEASE -FREE SURVIVAL WITH CURRENT DATA SUGGESTED THERE IS AN ADVANTAGE WHEN USING SURGICAL RESECTION VERSES ABLATIVE THERAPIES. AND HCC COMMONLY PRESENTS WITH ADVANCED TUMORS AND IN CHRONIC LIVER DISEASE. THEY BE SETTING, CHEMO EMBLY IZATION OR RADIO EMBLY IZATION ALONG CHEMOTHERAPY ALONG IN -- IN THE FORM OF SORAFENIB SORAFENIB IS THE BEST BENEFIT. I LOOK FORWARD TO ANSWER ANY QUESTIONS YOU MAY HAVE. >> THANK YOU VERY, VERY MUCH. >> CAN YOU COMMENT ON THE PRACTICE OF DOWN-STAGING? >> SURE. >> FOR TRANSPLANT? >> SO DOWN-STAGING REFERS TO PATIENTS WHO EXCEED MALIGNED CRITERIA THAT YOU, THEN, TYPICALLY USE EITHER RADIO EMBOLIZATION, MOST FREQUENTLY, OR A COMBINATION OF TACE AND RFA I DON'T KNOW ANYBODY THAT USES R FA ALONE. TO THEN SHRINK THE TUMOR SO THEY FALL WITHIN CRITERIA. AND SO THAT'S MORE COMMONLY NOW EMPLOYED FOR PATIENTS WHO FALL INTO THE UCFS CRITERIA. IT ALSO, I THINK BECAUSE THERE IS A WAITING PERIOD, GIVES YOU SOME IDEA OF BEHIND THE TUMOR BIOLOGY AS WELL. SO IN THE DOWN STAGE PROCESS, YOU OBLATE THE TUMOR BUT GENERAL LY WAIT 6 MONTHS BEFORE YOU WOULD DECLARE THAT PATIENT ELIGIBLE OR NON ELIGIBLE FOR TRANSPLANT. PATIENTS WHO ARE SUCCESSFULLY DOWN STAGE HAVE NO DIFFERENT OUTCOME, PROBABLY BECAUSE SOME OF THOSE PATIENTS THAT FELL WITHIN THE CRITERIA HAD AGGRESSIVE BEHAVIOR, WHERE YOU NOW SELECTED OUT PATIENTS IN THAT OTHER GROUP. SO REALLY, I THINK, LOOKING FOR PEOPLE LIKE YOURSELF TO REALLY GIVE US A MUCH BETTER, YOU KNOW, PROGNOSTIC INDICATOR BEHIND WHICH TIMER TUMORS ARE BEST SUIT ED TO TRY TO UNDERGO CUR ATIVE PROCEDURES LIKE THESE. >> THANK YOU. YOU MENTIONED DURING YOUR TALK THAT THE PERCENTAGE OF PATIENTS ON THE TRANSPLANT WAITING LIST WITH HCV CIRRHOSIS ARE FOLLOWING SECONDARY TO THE DIRECT ANTI VIRAL AGENTS. ARE PATIENTS NO LONGER GETTING ON THE WAIT LIST UNLESS THEY'VE SEEN DIRECT ANTIVIRAL AGENTS? THAT A REQUIREMENT NOW? SEND QUESTION IS, OBVIOUSLY IN IN THE SETTING OF HCV CIRRHOSIS CIRRHOSIS. AND THE SECOND QUESTION IS HOW DURABLE ARE THOSE RESPONSES FOR THOSE SEEING THE DAAs? >> WELL, THE ANSWER TO YOUR FIRST QUESTION IS CERTAINLY PATIENTS ARE GETTING ON A LIST ABOUT SEEING DIRECT ACTING ANTI VIRALS, BECAUSE THERE ARE A NUMBER OF REASONS. ONE REASON IS THAT THE COST OF THE ANTIVIRALS ARE VERY EXPENSIVE. AND MOST INSURANCE COMPANIES ARE -- HAVE S OME SORT OF GATE TO DISPENSE THE MEDICATIONS. SO THERE IS A PROCESS. SO OF ALL THE 4 MILLION PATIENTS IN THE U.S., PROBABLY ABOUT MAYBE 300,000 OR SOME SOV BEEN TREATED TO DATE. DRUGS HAVE BEEN APPROVED FOR 3 YEARS OR SO, 4 YEARS. SO THERE IS A LIMITATION BASED UPON THE ACCESS TO THE MEDICATION. AND THEN FOR PATIENTS THAT HAVE THE COMPENSATED CIRRHOSIS, MANY OF THOSE PATIENTS, CIRRHOSIS IS NOT GOING TO BE NECESSARILY IM PROVED BY TREATING THEM AT THAT POINT. NOW, ALL THOSE PATIENTS PRESUMABLY WOULD BENEFIT FROM BEING TREATED POST TRANSPLANT BECAUSE THE VIRUS DOESN'T GO AWAY, JUST BECAUSE YOU PUT A NEW ORGAN IN. AND THE WORST THING TO DO IS PUT AN ORGAN IN AND HAVE THAT GET RE INFECTED. IT WOULD CERTAINLY HAVE A ROLE, I WOULD SAY ALL PATIENTS WHO HAVE NOT BEEN TREATED PRE TRANSPLANT, NOW DAYS ARE LIKE LY TO BE TREATED POST TRANSPLANT. >> GREAT TALK. I HAVE TWO QUESTIONS. THE FIRST, CONTINUATION WITH HIS FOR PATIENTS WITH FCC HEPATITIS C, IS THERE A CERTAIN MELD SCORE AT WHICH YOU DECIDE THAT THIS PATIENT WOULD PROBABLY BENEFIT FROM GETTING DAA THERAPY RATHER THAN GET EVALUATED OR GET PUT ON THE TRANSPLANT LIST, AND IF THEY DO GET THE DA THERAPY AND THEY HANG AT BEING NOT ELIGIBLE FOR A TRANSPLANT, BUT NOT BEING ABLE TO HAVE A GOOD QUALITY OF LIFE EITHER, SO DO YOU HAVE A SAY OR THOUGHT ABOUT WHAT MELD CUT OFF WOULD BE? >> YEAH. SO I'LL LET JAKE TAKE PART OF THAT QUESTION AS WELL. THE APPROPRIATE PATIENT, AT WHAT POINT YOU SHOULD BEST TREAT PATIENTS WITH THE ANTIVIRALS. YES, WE KNOW A MELD SCORE OF 15 IS THE NUMBER OF WHICH THE BENEFIT OF TRANSPLANT OUTWEIGHS THE RISK OF THE TRANSPLANT ITSELF. AND BECAUSE OF THAT, THERE ARE MANDATORY SHARING POLICIES, BOTH BELOW 15 AS WELL AS ABOVE 35. IN REALITY, THERE ARE EXCEPTIONS TO THE RULE. FIFTEEN IS THE NUMBER AT WHICH THE BENEFIT COMES INTO PLAY. MOST TIMES, YOU WOULD NOT TRANS PLANT SOMEONE WHO HAS A MELD LOWER THAN THAT, WITH THE EXCEPTION OF PATIENTS WHO HAVE H CC. AND SOME OF THOSE PATIENTS HAVE NORMAL MELD SCORES ALL TOGETHER, BUT THERE INDICATION IS NOT DRIVEN BY THE MELD BUT THE UNDER LYING CANCER. YOUR SECOND THING WAS ABOUT THE DURABILITY OF THE TREATMENTS. AND AS BEST WE KNOW, ALTHOUGH THE TREATMENTS WERE APPROVED ON THE BASIS OF SUSTAINED VIR OLOGICAL RESPONSES AT 12 WEEK S, THAT THE -- THAT THESE PATIENTS ARE THEORETICALLY CURED THAT THE RECURRENCE RATE, AND JAKE, YOU CAN COMMENT 0 ON, THIS AFTER FULL COURSE, PARTICULARLY PATIENTS WHO HAVE A NON CEROTIC ENVIRONMENT. ARE VERY DURABLE. JAKE, DO YOU WANT TO COMMENT POR ON THAT? >> WHAT ABOUT THE QUESTION IN REGARD TO WHEN TO TREAT PATIENTS >> EVENING I THINK WE ALL KNOW CIRRHOSIS IS A NEGATIVE TREATMENT FACTOR. SO IT'S A CATCH 22. THOSE PEOPLE THAT NEED TREATMENT TEND TO RESPONSE -- RESPOND LESS WELL. ON THE TRANSPLANT LIST, PATIENTS CAN BE DELISTED AFTER THEY'RE TREATED WITH SUSTAINED RESPONSE. FOR THESE PATIENTS IT'S G THEY CAN BE DELISTED. THEY HAVE LOWER MELD AND THEY TEND TO DO PRETTY WELL AFTER THEY ARE -- THE VIRUS IS RAD ICATED. SO I THINK IT'S -- YOU HAVE TO SELECT. I THINK IT'S NOT CLEAR AT THIS POINT WHO CAN BENEFIT FROM IT. I THINK IT'S MORE EXPERIENCE GABEED FROM TREATING THESE PATIENTS -- ESPECIALLY THE CIRRHOSIS, WE'LL HAVE A BETTER IDEA WHO CAN BENEFIT FROM TREATMENT VERSES STAY ON THE WAITING LIST. >> YOU WANT TO COMMENT ABOUT LIVING DONORS? >> SURE. SO THE INTERESTING THING ABOUT LIVING DONORS, IT WAS A TRIAL THAT WAS SPONSORED BY THE NIH LOOKING AT LIVING DOABER LIVER TRAN PLANTATION. THE IDEA BEHIND THAT WAS THAT YOU TELL ME THAT PATIENTS, IF YOU DO AN INTENT TO TREAT ANALYSIS, DON'T DO AS WELL. THEY HAVE TO SIT ON THE WAITING LIST. IF IF YOU GET THEM A DONOR RIGHT AWAY? MAYBE THOSE PATIENTS WOULD DO BETTER. AND SO IT REALLY BECAME POPULAR TO DO LEAVING DONOR LIVER TRANS PLANTATION WHERE YOU TAKE OUT THE RIGHT LOBBY FROM A DONOR AND TRANSPLANT THAT INTO AN ADULT. ATC WAS ONE OF THE COMMON INDICATIONS. WHAT THAT TRIAL SHOWED IS THAT THERE ACTUALLY WAS A HIGHER RECURRENCE RATE WHEN YOU DID LIVING DONOR TRANSPLANTS IN PATIENTS WITH HCC. PROBABLY HAS TO DO WITH THE FACT THAT THE ACTUAL NATURE OF THE EX PLANT OF THE TUMOR WHERE YOU HAVE TO PRESERVE THE VENA CAVA TO SUE THE LIVER ON TO PLAYED A ROLE. ONE OF THE THINGS WE KNOW, IF YOU SELECT PATIENTS BY HAVING THAT FACT THAT MULTI -- MANY PATIENTS DROP OUT, YOU END UP WITH BETTER RESULTS. SO IF YOU TRANSPLANT PATIENTS WITH HCC TOO QUICKLY, YOU'RE GOING TO TRANSPLANT PATIENTS THAT HAVE AGGRESSIVE BEHAVIOR AS WELL AS NOT AGGRESSIVE BEHAVIOR. SO WITH THE MESH YOU'D END UP WITH POTENTIALLY POORER OUTCOMES I THINK THAT PLAYED INTO A ROLE. WHEN YOU CARE IT TO [INDISCERNIBLE] DONOR TRANSPLANTS, THOSE -- ALL THOSE PATIENTS WAITED ON THE LIST. SO THERE WAS A NATURAL SELECTION PROCESS FOR BETTER BEHAVING BIOLOGY THAN THOSE THAT HAD A LIVE DONOR TRANSPLANTS AND COULD GET TRANSPLANTED RIGHT AWAY. >> WHEN IT COMES TO NOT HEPATITIS, BUT CHILDREN'S DISEASES, INHERITABLE DISORDERS -- >> STILL PLAY A BIG ROLE AND PARTICULARLY, I THINK, IT PLAYS SIGNIFICANT ROLE FOR CHILDREN, FOR TWO REASONS. ONE, THE AMOUNT OF LIVER YOU HAVE TO TAKE OUT IS SMALLER. THE RISK TO THE DONOR IS MUCH LESS. THERE HAVE BEEN AT LEAST -- AT LEAST FIVE DONOR DEATHS RELATED TO LIVE DONOR RIGHT LOBE DO NATION, WHEREAS -- I DON'T REALLY RECALL ANYBODY HAVING A DONOR DEATH FROM A LEFT LATERAL SEGMENT WHICH IS WHAT YOU NEED FOR A CHILD. SECOND TO THAT, MOST ADULT ORGAN DONORS ARE -- MOST ORGAN DONORS A ARE ASSAULTS -- INCOME [TECHNICAL DIFFICULTIES]. HOW OFTEN, YOU CAN SPLIT A CONER INTO TWO PIECES AND USE THE SECOND PIECE FOR THE CHILD. BECAUSE THE IMMEDIACY OF THE NEED AND AS WELL AS THE LOW MORBIDITY, GENERALLY SPEAKING, LEFT LATERAL SEGMENT SHOULD BE STRAIGHT FORWARD. >> MY RECOLLECTION IS THAT IN THE EARLY DAYS, THE SURGERIES TOOK OVERNIGHT, MAYBE 10-12 HOUR S. THEY USED 100 UNITS OF BLOOD. WHAT ARE YOU USING NOW? HOW LONG DOES IT TAKE? >> YEAH, YOU KNOW, THE MAJORITY OF THE PATIENTS NOW DON'T EVEN REQUIRE A SINGLE TRANSFUSION. IT'S NOT BECAUSE WE'RE THAT MUCH BETTER THAN TOM. IT'S BECAUSE WE ARE NOT TRANS PLANTING PATIENTS AT THE END OF THEIR PORTAL HYPERTENSION AND END STAGE ANYMORE, PARTICULARLY YOU LOOKED AT THE LIST WHERE HALF THE PATIENTS WERE HCC WITH NORMAL MELDS. IT'S LIKE DOING A GALLBLADDER MEDICATION. NO PORTAL HYPERTENSION. IF YOU HAVE NO PORTAL HYPERTENSION IT'S A FAIRLY STRAIGHT FORWARD OPERATION. IT'S WHEN YOU GET SIGNIFICANT DE COMPENSATED CIRRHOSIS WHERE THE BLEEDING COMES INTO PLY. I REMEMBER A FUNNY STORY THAT MY MENTOR TOLD ME. IN THE OLD DAYS, THE ORGAN WAS ONLY VALID FOR 6 HOURS, SO YOU HAD TO HAVE TWO TEAMS. A TEAM THAT STARTED TO TAKE THE ORGAN OUT AND A TEAM THAT PROCURED THE ORGAN. IT WAS ALMOST LIKE A FRATERNITY. TOM WOULD TRAIN THESE GUISE. THEY WOULD START PROGRAMS. THEN THE FIRST TRANSPLANT, YOU WOULD GO OUT AND SAY CALL ME. HE WOULD FLY OUT, PROCURE THE ORGAN, BRING IT BACK, MAKE SURE THAT FIRST TRANSPLANT WENT WELL. AT THIS POINT, TOM WAS LIKE A CULT FIGURE. HE WAS ON THE COVER OF TIME, THROWING OUT THE BALL AT THE WORLD SERIES, 60 MINUTES. EVERYONE KNEW WHO HE WAS. SO MY MENTOR, HE'S IN THE OPERATING ROOM WITH HIS TEAM. TOM IS OUT PROCURING THE ORGAN. HE CALLS IN TO THE OPERATING ROOM, THE NURSE ANSWERS. SAYS HI, THIS IS DR. STOSSEL, CAN YOU PLEASE TELL DR. JENKINS WE HAVE THE ORGAN AND ON OUR WAY BACK. SHE PAUSED, SHE SAYS CAN YOU SPELL THAT FOR ME, PLEASE? [LAUGHTER] HE LOVED TO TELL THAT STORY. >> HOW LONG DOES A TRANSPLANT TAKE THESE DAYS. >> ABOUT FIVE OR SIX HOURS. OF THAT TIME, AN HOUR OR TWO IS JUST THE ANESTHETIC PORTIONOF IT, GETTING A PATIENT PREPARED AND LINES AND SO FORTH FOR THE HEMODYNAMIC PROCESS. AND I THINK OF ALL THE THINGS THAT HAVE IMPROVED, THAT'S PROBABLY THE SINGLE THING THAT'S BEEN THE MOST SIGNIFICANT IS THE PERIOPERATIVE CARE OF THE PATIENT, QUITE DIFFERENT THAN WHEN TOM AND THOSE GUYS WERE DOING IT IN PITTSBURGH IN THE 80 s. >> ONE OTHER QUESTION, STOSSEL MAY BE INITIATED THE IMMUNO SUPPRESSION. LATE YOUR HE WAS THE ONE SAYING LET'S NOT DO IMMUNOSUPPRESSION, PATIENTS DO BETTER. >> RIGHT. >> WHERE DOES THAT STAND NOW? THERE WAS A LOT OF RAPID FIBROSIS PROGRESSION POST TRANSPLANT THAT WAS PROBABLY DUE TO THE IMMUNOSUPPRESSION IN A WAY. >> WELL, TOM DID NOT -- HE DID NOT DISCOVER THE IMMUNO SUPPRESSION. THE FIRST GROUP MOST POPULAR CAME OUT OF MINNESOTA, ANOTHER BIG TRANSPLANT PROGRAM, CALLED MINNESOTA ALG. IT BECAME SCANDALOUS, THEY WERE SELLING IT, PROFIT, ALL THAT KIND OF STUFF. IT WAS THAT. BUT TOM WAS A BIG PRO OPPONENT OF FK506, REALLY THE DRUG THAT IS CURRENTLY USED. AND THEN MASS, I THINK, REALLY TRANSFORMED NOT ONLY LIVER TRANSPLANTATION BUT OTHER SOLID ORGAN TRANSPLANTS. TOM BELIEVED IN THIS CHIMERIC PROCESS THAT OCCURRED THAT YOU AND YOUR ORGAN LIVED IN SYMP B IOSIS. THEY WERE BOTH CELLS FROM BOTH THE DONOR ORGAN AND FROM YOU THAT WAS PART OF YOUR MAKEUP. HE WAS ABLE TO IDENTIFY KENTUCKY MERIS, BUT NOT EVERYBODY IS CHIMERIC. SO I THINK THAT AS A RESULT OF HIS TRIALS, MOST PEOPLE BELIEVED THAT YOU CAN CERTAINLY LOWER IMMUNOSUPPRESSION. THE FURTHER YOU'RE OUT FROM YOUR TRANSPLANT, THE LEST YOU NEED. ULTIMATELY IT'S STILL VERY DIFFICULT TO DETERMINE WHO CAN COME OFF IMMUNOSUPPRESSION ALL TOGETHER ABOUT JUST BLIND TRIAL OF SLOWLY DECREASING IT UNTIL SOMEBODY THAT IS AN EPISODE OF REJECTION, THEN YOU KNOW THAT THAT PATIENT ENDS UP NEEDING IT BACK ON. BUT BECAUSE OF THE CONSEQUENCES OF CHRONIC REJECTION, MOST PATIENTS STAY ON SOME LEVEL OF IMMUNOSUPPRESSION THROUGHOUT THEIR LIFE. >> I HAVE A SIMPLE QUESTION. DO YOU LOOK AT THE AGE OF THE DONOR VERSUS THE PATIENT, DOES IT HAVE TO BE THE SAME AGE, YOUNGER, OLDER? HOW DOES IT WORK? >> I'M LAUGHING BECAUSE WHEN I FIRST STARTED WHICH WAS IN THE 1991 OR 1992, THE -- WHAT WAS CONSIDERED AN OLDER DONOR WAS OVER THE AGE OF 40, WAS CONSIDER ED AN OLDER DONOR. AND SO TO ANSWER YOUR QUESTION, IS THAT -- ONLY FOR PROBABLY CHILDREN DO WE PLAY A BIG ROLE, CHILDREN OR VERY UNION ADULTS. THE -- BUT FOR THE AVERAGE ADULT , AGE DOES NOT PLAY AS BIG A ROLE. I WOULD SAY THAT THE OLDER DONOR S WE DO KNOW A FEW THINGS. ONE IS THAT THEY DONOR TRANSPLANTS TOLERATE REJECTION AS WELL AS YOUNGER DONORS. PARTICULARLY FOR PATIENTS WHO ARE AT -- WHO WERE HEPATITIS C IN PARTICULAR, YOU WOULD TEND NOT TO USE OLDER DONORS. YOU WANT TO LOWER THE IMMUNO SUPPRESSION SO THE VIRUS STAYS UNDER CONTROL. THIS WAS PREANTIVIRALS. BUT YOU DON'T WANT TO LOWER IT SO MUCH THAT YOU DIDN'T GET REJECTION IN THE OLDER LIVER AND HAVE THAT BURN OUT. BUT NOW DAYS, THE LENGTH OF TIME THE WAITING TIME THAT YOU CAN TRANSPLANT A LIVER IS PROBABLY ANYWHERE FROM 12-24 HOURS. THE OLDER IT IS, YOU WANT TO STEER TOWARD KEEPING IT SHORTER THAN THE 12 HOURS AS OPPOSED TO TRYING TO TRANSPLANT SOMETHING LATER ON. >> SO CERTAINLY ONE OF THE CHALLENGES FOR YOUNG SCIENTISTS AND TRAINING Ph.D.s, IN PARTICULAR, BUT MDs, IS TO TRY AND THE MECHANISM WHEREBY THE LIVER DETERIORATES WHEN ITS OUT OF THE BODY AND WHAT CAN BE DONE TO MAINTAIN IT FOR LONG PERIODS OF TIME, SUCH AS HAVE BEEN ACCOMPLISHED WITH KIDNEY. ANYWAY -- SO LISTEN. I WANT TO THANK BOTH OF YOU FOR A VERY, VERY EXCITING PRESENT ATION AND I'M SURE I'M SPEAKING ON BEHALF OF EVERY ONE. THANK YOU VERY MUCH FOR COMING. [APPLAUSE]