TODAY WE ARE VERY FORTUNATE TO HAVE TWO COLLEAGUES HERE AT NIH WHO ARE VERY MUCH IN THE NATIONAL AND INTERNATIONAL LIMELIGHT WHEN IT COMES TO KNOWLEDGE ABOUT PRIMARY CANCER OF THE LIVER. AND OTHER THINGS. IT WASN'T TILL TERRIBLY LONG AGO, I GUESS THAT IS RELATIVE TO HOW OLD YOU ARE, BUT IT WASN'T SO TERRIBLY LONG AGO THAT PRIMARY CANCER OF THE LIVER, IF IT APPEARED IN A PATIENT IN THE UNITED STATES, THAT PATIENT WOULD BE PRESENTED AT GRAND MEDICAL ROUNDS BECAUSE IT WAS SO UNUSUAL AND AT THE SAME TIME ON THE OTHER SIDE OF THE PACIFIC, IF SOMEONE HAD AN ACUTE MYOCARDIAL INFARCTION, THEY WOULD BE PRESENTED AT GRAND MEDICAL ROUNDS BECAUSE IT WAS RARE IN CHINA AND JAPAN WHEREAS CANCER OF THE LIVER WAS THE SECOND-MOST COMMON CANCER AND HOSPITALS WERE FILLED WITH THESE PATIENTS. WELL, THE SITUATION HAS SYSTEMATICALLY CHANGED DUE TO MANY FACTORS WHICH WE WILL DISCUSS TODAY AND THE OUTCOME IS NOW IN THE UNITED STATES IT IS ANINCREASINGLY RECOGNIZED MAJOR CHALLENGE WHEN IT COMES TO DIAGNOSIS AND THERAPY. NOW, SO I JUST WANT TO MAKE A COUPLE OF POINTS FROM A CLEARLY CLINICAL PERSPECTIVE BECAUSE THESE ARE NOT OFTEN MADE WHEN PEOPLE TALK ABOUT LIVER CANCER WHERE THE MAJOR FOCUS, WHICH WE'RE GOING TO HEAR ABOUT TODAY, HAS TO DO WITH THE APPLICATION OF GENOME SCALE ANALYSIS OF CANCER AS AN ATTEMPT TO IDENTIFY BOTH MARKERS, MECHANISMS AND SO FORTH. SO THE RESEARCH HAS BECOME INCREASINGLY CELLULAR AND REDUCTIVE BUT FOR THOSE WHO DON'T DEAL WITH PATIENTS, YOU MIGHT FIND A FEW FACTS INTERESTING. ONE, THE LIVER CONSTITUTES ABOUT 5 PERCENT OF YOUR BODY WEIGHT AND IT IS ABOUT THE SIZE OF A FOOTBALL AND IT IS TUCKED UNDER YOUR RIGHT RIB CAGE. NOW, THE ONLY SENSORY NERVES THAT ARE IN THE LIVER ARE ON THE SURFACE. IT IS WRAPPED IN A CAPSULE AND THAT IS IMPORTANT BECAUSE A LOT CAN BE GOING ON INSIDE THIS ORGAN WITHOUT PRODUCING PAIN AND IT IS ONLY WHEN THE CAPSULE IS INVOLVED THAT PATIENTS COMPLAIN OF PAIN. AND THE CAPSULE GETTING INVOLVED IS USUALLY LATE IN THE DISEASE. THE OTHER THING IS THE SYMPTOMS ARE USUALLY LATE AND THEY WOULD DEPEND UPON WHEN THE TUMOR FORTUITOUSLY INTERFERES WITH THE BILIARY SYSTEM WHERE THEY MAY BECOME JAUNDICED OR THE VASCULAR SYSTEM WHERE THEY ARE BLEEDING. SO WE DON'T USUALLY DIAGNOSED CANCER IN THE LIVER AT A VERY EARLY STAGE. WELL, THAT IS UNDERGOING REVISION AND YOU WILL HEAR ABOUT IT TODAY. THE OTHER IMPORTANT AND INTERESTING THING TO THINK ABOUT IS WHY IS ALMOST ALL PRIMARY CANCER OF THE LIVER DRUG RESISTANT, EVEN IN PATIENTS WHO NEVER HAD ANY DRUGS? AND THAT IS A VERY CHALLENGING AND INTERESTING QUESTION WHICH, IF YOU WISH, WE CAN DISCUSS IN THE QUESTION PERIOD. AND LASTLY AND MOST IMPORTANT IS PRIOR TO THE ABILITY TO PERFORM LIVER TRANSPLANT IN SELECTED PATIENTS WITH LIVER CANCER, THE TREATMENT OUTCOME IS VERY POOR. SO LET ME QUICKLY SHOW YOU SOME EXAMPLES. THIS IS WHAT THE HUMAN LIVER LOOKS LIKE AND I DON'T KNOW IF ALL OF YOU HAVE EVER SEEN ONE. IT IS NOT A VERY DISTINGUISHED-LOOKING ORGAN. IT IS NOT AS ROMANTIC AS THE HEART OR AS CURVED AS THE KIDNEY, YOU KNOW. IT IS THE BIGGEST SOLID ORGAN IN THE BODY AND IT IS BASICALLY A VASCULAR ORGAN SO HERE IS THE VENOUS SYSTEM IN THE PURPLE, THE RED, THE ARTERIAL SYSTEM, THE GREEN IS THE BILIARY SYSTEM AND WHAT IS IN BETWEEN ARE THE HEPATOCYTES WHICH ARE ONE OF SIX CELL TYPES IN THE LIVER AND THE DOMINANT ONE AND THAT IS WHERE THESE CANCERS DEVELOP. SO YOU SEE WHAT I MEAN. YOU HAVE TO HAVE A TUMOR AND YOU DON'T HAVE PAIN AND IT IS IN THE MASS OF THE LIVER, IT HAS TO INTO FEAR WITH THE VASCULAR SYSTEM OR THE BILIARY SYSTEM TO DO ANYTHING. NOW, THIS IS WHAT THE CANCER LOOKS LIKE IN THE PHOTOMICROGRAPH AND YOU CAN EASILY TELL THE MALIGNANT CELLS ON THE RIGHT AND THE NORMAL MALL ONES ON THE LEFT BUT THEY ARE ALL INFILT TRAITING AND THE PICTURE ON THE BOTTOM IS THE REASON I PICKED THIS BECAUSE THAT IS A BIG CANCER SITTING THERE ON THE EDGE AND IT IS THROUGH THE CAPSULE, SO THAT PATIENT PROBABLY FELT IT AND HAD PAIN BUT OTHERWISE, IT COULD BE THERE AND YOU WOULDN'T EVEN KNOW IT WAS THERE. HERE IS THE DISMAL SURVIVAL -- THIS IS DATED 1996 AND YOU WILL SEE FROM 1977 UNTIL 1996 THAT DESPITE ALL KINDS OF STUDIES, TREATMENTS AND SO FORTH, THE SURVIVAL IS PRETTY DISMAL. THAT IS NOT THE CASE TODAY FOR REASONS THAT ARE GOING TO BE DISCUSSED. NOW, ONE OF THE DRAMATIC EXAMPLES OF THIS IS THAT PRIMARY LIVER CANCER, MOST OF THE TIME, NOT ALL THE TIME, IS ASSOCIATED WITH CHRONIC VIRAL INFECTION, HEPATITIS B AND HEPATITIS C. AND THIS IS AN EXAMPLE WHERE VACCINATION PROVED TO BE THE BEST ANTICANCER TREATMENT THAT& EXISTED. ON THE TIME LINE, PRIMARY LIVER CANCER WAS VERY COMMON, EVEN IN CHILDREN AND IT WAS DUE TO HEPATITIS B WHICH WAS ENDEMIC IN TAIWAN. AND WITH THE DEVELOPMENT OF HEPATITIS B VACCINATION WHEN THESE CHILDREN WERE VACCINATED, YOU SEE HERE IN A PERIOD STARTING IN 1981 TO 1994, THE ANNUAL INCIDENCE OF LIVER CANCER WAS REDUCED AT 50 PERCENT AND AFTER 1994, I THINK IT HAS BEEN ALMOST COMPLETELY ERADICATED DUE TO HEPATITIS B. BUT WE HAVE ANOTHER VILLAIN ON THE SCENE WHICH IS HEPATITIS C THAT HAS SOME OF THE SAME EFFECT. SO THIS IS THE ONLY EXAMPLE, CERTAINLY THE FIRST AND THE ONLY EXAMPLE WHERE ON THE LARGE SCALE VACCINATION AGAINST A VIRUS, ACTUALLY, THE LETHAL CANCER. SO AS I MENTIONED IN THE BEGINNING, WE'RE VERY EXCITED TO HAVE TWO EXPERTS IN THIS FIELD. SO THE FIRST ONE IS MARC GHANY WHO GOT HIS MEDICAL DEGREE IN SCOTLAND, CAME HERE TO TULANE AND IS A STAFF CLINICIAN AND AN ELEGANT LOOK THAT IS INTERNATIONALLY RECOGNIZED IN THE CLINICAL TRANSLATION. HE IS A CLINICAL INVESTIGATOR, DEALING MAINLY WITH HEPATITIS B, HEPATITIS C AND AS YOU WILL SEE HERE, SOME OF ITS COMPLICATIONS. OUR SECOND SPEAKER IS ANURADHA BUDHU WHO IS A PHD IN THE NATIONAL CANCER INSTITUTE WHERE SHE IS AN ASSOCIATE SCIENTIST IN A LABORATORY OF HUMAN CARCINOGENESIS. NOW, SHE CAME HERE TO CORNELL IN 2002. HER WORK IS WIDELY REKNOWN AND QUOTED FOR LIVER CANCER IN AN ATTEMPT TO DEVELOP MARKERS FOR EARLY DIAGNOSIS, MECHANISMS AND WHAT DIFFERENTIATES THOSE TUMORS THAT ARE GOING TO METASTASIZE FROM THOSE THAT AREN'T. AND SHE WORKS IN A LARGE CONSORTIUM, A NATIONAL EPIDEMIOLOGY GROUP WHICH WE WILL HEAR ABOUT IN TERMS OF THEIR RESULTS. NOW, IN ADDITION, WE'RE EXTREMITILY GRATEFUL THAT Dr. GHANY HAS BROUGHT A PATIENT WHO WAS KIND ENOUGH TO BEGIN THE SESSION AND TELL YOU ABOUT HIS DISEASE. SO MARC, YOU WANT TO INTERVIEW? I HAVE WITH ME TODAY MR. GUY CLEESE, HE IS A PATIENT I HAVE KNOWN FOR CLOSE TO 20 YEARS NOW AND HE UNFORTUNATELY DEVELOPED HEPATOCELL CARCINOMA AND HE IS HERE TO TELL YOU A LITTLE ABOUT HIS STORY AND PUT A FACE TO THIS DISEASE. SO MAYBE, MR. CLEESE, YOU CAN TELL US A LITTLE BIT ABOUT HOW YOU FOUND OUT ABOUT YOUR CONSUMER -- TUMOR AND THEN WHAT WAS DONE? [ DISCUSSION OFF MIC ] >> HELLO, MY NAME IS GUY CLEESE. I GOT OUT OF HIGH SCHOOL IN NEW YORK CITY IN 1969. I WENT FOR A JOB ON A SHIP, WENT FOR A PHYSICAL, THEY SAID YOU ARE NOT GOING TO SEA, SON, YOU HAVE HEPATITIS. SO I WENT UP TO WEST POINT MILITARY HOSPITAL AND STAYED THERE. AT THE TIME, THE TREATMENT WAS SIMPLY BED REST AND EAT A LOT OF STARCH AND THEN IT WENT AWAY AND REALLY DIDN'T GIVE ME ANY PROBLEMS, EVER. IN THE MID-80s, I DECIDED TO HAVE MAYBE SOMEONE TAKE A LOOK AT MY LIVER AGAIN AND THERE WAS A DOCTOR HERE IN D.C. AND HE SAID WE'LL JUST MONITOR THE SITUATION. AND THEN I THINK IT WAS AROUND 1990, I WENT IN FOR ACTUALLY TREATMENT FOR INTERFERON AND -- YES? I'M SORRY, I WENT IN TO SEE A DOCTOR AROUND 1990, 91 AND THEY PUT ME ON INTERFERON & RIBOVIRIN WENT THROUGH THE TREATMENT, IT DIDN'T WORK AND HE RECOMMENDED I APPROACH NIH TO SEE ABOUT A PROTOCOL. SO I STARTED WITH TWO OF Dr. GHANY'S PREDECESSORS AND THAT WAS LOW DOSAGE INTERFERON FOR A LONG PERIOD OF TIME. I DID CLEAR THE VIRUS TWICE BUT IT CAME BACK SO THAT DIDN'T REALLY WORK BUT IT DID HELP MY LIVER, THE CIRRHOSIS. AFTER THAT, BY THEN I WAS UNDER Dr. GHANY'S CARE AND THEN WE WENT TO THE HIGH DOSAGE PEG AND HIGH DOSAGE RIBAVIRIN AND IT CAME BACK. THEN WE TRIED ANOTHER REGIME, AND AGAIN I CLEARED THE VIRUS AND ARE AGAIN IT CAME BACK. AND THEN FINALLY IN 19 -- 2017, BEGINNING OF 2016, I WENT ON ANOTHER DRUG AND DID THE STANDARD TREATMENT THERE AND THE VIRUS CLEARED. UNFORTUNATELY, SOMEWHERE BETWEEN 2012 AND 2017, A CYST WAS NOTICED ON MY LIVER BY THE MRIS DONE BY THE DOCTOR AND THEY KEPT MONITORING THAT AND THEN AS SOON AS I CLEARED THE VIRUS WITH THE VOCEFI, THIS WAS IN 2017 RIGHT AFTER THANKSGIVING, THEY SAID THE CYST IS NO LONGER A CYST, IT IS NOW A TUMOR AND Dr. GHANY SAID YOU ARE NOW A CANDIDATE FOR LIVER TRANSPLANT. SO I HAD A LIVER TRANSPLANT NOVEMBER 26, 2018 AND EVERYTHING SEEMED TO BE GOING WELL BUT THE PATHOLOGY REPORT THAT SHOWED THE TUMOR, NOT A VERY LARGE TUMOR ON THE SURFACE BUT IT WAS DEEP AND WENT INTO VASCULAR -- WENT INTO THE VEINS. SO NOW THE CONCERN IS SOME OF THESE LIVER CANCER CELLS COULD BE CIRCULATING THROUGH MY BODY. SO I AM SEEING AN ONCOLOGIST NOW AT JOHNS HOPKINS PLUS THE LIVER TRANSPLANT TEAM. PERSONALLY, I HAVE NEVER HAD ANY BAD EFFECT. I WAS ALWAYS ABLE TO WITHSTAND THE DRUGS THAT Dr. GHANY THREW AT ME, PRETTY WELL, NEVER ANY BAD SIDE EFFECTS OR ANYTHING LIKE THAT AND LIKE I SAID, I CLEARED THE VIRUS FOUR TIMES AND IT CAME BACK FOUR TIMES AND I THINK THAT IS ABOUT IT. OH, AND IF YOU ARE INTERESTED, MY AGE IS 67. >> HOW MANY MONTHS YOU UNDERWENT TREATMENT -- >> THE FIRST TIME IT CAME BACK, IT CAME BACK QUITE NOTICEABLY. NOT VERY LONG, NOT VERY LONG AT ALL. I WOULD SAY NEVER MORE THAN THREE OR FOUR WEEKS >> SO THE TUMOR WITH THE VIRUS, WOULD BE INTERESTING IS 1B OR 1A >> 1A. [OFF MIC ] >> SO YOU HAD HEPATITIS B AND CIRRHOSIS? >> CORRECT. >> WERE YOU AWARE OF THAT? THAT IS A SERIOUS PROBLEM. WERE YOU SHOWING ANY SIGNS OF LIVER PROBLEMS? >> NO, I NEVER HAD ANY BAD SIDE EFFECTS BUT BECAUSE I WAS DIAGNOSED WITH HEPATITIS, I KNEW I HAD HEPATITIS AND THAT IS WHY IN 1980 I DECIDED TO LET SOMEONE TAKE A LOOK AT MY LIVER AND SEE -- >> WHAT IS YOUR WORK, WHAT DO YOU DO? >> MY WORK NOW? >> WELL, WHAT IS YOUR CAREER. >> MERCHANT MARINE, BEEN TO TAIWAN AND THOSE PLACES MANY TIMES AND NOW I AM A HARBOR PILOT IN SAN FRANCISCO. A SHIP'S PILOT IN IT SAN FRANCISCO. >> SO YOU HAVE BEEN ABLE TO WORK CONSISTENTLY EXCEPT WHEN YOU HAD THE TRANSPLANT, I PRESUME? >> YES, NEVER HAD ANY HARSH SIDE EFFECTS EVEN WITH THE HARSHEST STUFF Dr. GHANY THREW AT ME. >> ANY OTHER QUESTIONS? OKAY, THANK YOU VERY MUCH, YOU ARE VERY KIND TO COME IN AND WE CERTAINLY WISH YOU EVERY SUCCESS. >> THANK YOU SO MUCH, MR. CLEESE AND UNFORTUNATELY, HIS STORY IS NOT VERY DIFFERENT FROM MANY OTHER PATIENTS SO MAYBE THIS IS A GOOD SEGUE INTO THE TALK. SO FIRST, I WOULD JUST LIKE TO THANK WIN FOR THE OPPORTUNITY TO COME AND SPEAK TODAY AND ALSO AGAIN TO MR. CLEESE AND HIS WIFE WHO ARE AGREEING TO COME AND SHARE HIS STORY WITH YOU. SO WIN ASKED ME TO TALK A LITTLE ABOUT THE CHANGING EPIDEMIOLOGY OF THIS CANCER AND TALK A LITTLE ABOUT DIAGNOSIS, STAGING AND TREATMENT AND THIS WILL SET THE STAGE FOR THE NEXT SPEAKER. SO AS LYNN TOLD YOU, THIS IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND UNFORTUNATELY, THE SECOND HIGHEST CAUSE OF CANCER RELATED DEATHS. IN 2017, THE ESTIMATED PREVALENCE OF OVER 800,000 CASES WORLDWIDE BUT THE INCIDENCE VARIOUS GEOGRAPHICALLY FROM A HIGH OF 15 TO 100,000 IN ASIA AND SUBSAHARA AFRICA TO 15 IN MEDITERRANEAN, SOUTHERN EUROPE AND CENTRAL AMERICA AND LOWEST, LESS THAN 100,000 IN NORTHERN EUROPE. MORE THAN 80 PERCENT OF CANCERS OCCUR IN ASIA AND SUBSAHARAN AFRICA AND IT IS RELATED TO AFLATOXIN B1 EXPOSURE. SO THESE ARE THE CANCER RATES OF MEN AND WOMEN THROUGHOUT THE COUNTRY AND DURING THE PERIOD 2003 TO 2007, THE HIGHEST INCIDENTS WERE IN EAST AND SOUTHEAST ASIA OF HCC AS YOU SEE IN THE TOP BAR AND LOWEST RATES WERE IN NORTHERN EUROPE. I ALSO WANT TO BRING TO YOUR ATTENTION THE NOTABLE GENDER DISPARITY IN THIS CANCER. IF YOU LOOK AT THE BARS, THE MALES ARE SHOWING ON THE LEFT SIDE, FEMALES ON THE RIGHT SIDE AND THE INCIDENCE IN MALES IS ABOUT IT 2 TO 3 TIMES COMPARED TO FEMALES, REGARDLESS OF WHAT COUNTRY YOU LOOK AT. SO MEN SEEM TO HAVE AN INCREASED RISK ABOVE WOMEN DESPITE HAVING THE SAME ETIOLOGY. THIS IS DATA FROM THE GLOBAL DISEASE PROJECT SHOWING DATA FROM 2017 WHERE THE GLOBAL PREVALENCE WAS ESTIMATED OVER WILL-- 800,000 CASES AND ALSO THE ETIOLOGY OF THE CANCER AND HEPATITIS B ACCOUNTS FOR ALMOST HALF OF ALL CANCER LIVERS THAT OCCUR GLOBALLY AND HEPATITIS ACCOUNTS FOR 70 PERCENT OF ALL HCC'S. ALCOHOLIC AND NONALCOHOLIC DISEASE ACCOUNT FOR 20 PERCENT AND THEN THESE CONDITIONS ALL ASSOCIATED WITH WITH CIRRHOSIS. SO WHAT ABOUT THE U.S. DATA? THIS IS UPDATED DATA SIMILAR TO WHAT LYNN SHOWED YOU IN HIS INTRODUCTION. THIS IS DATA FROM THE DATABASE SHOWING AGE-ADJUSTED INCIDENCE RATES OF CANCER AND LYMPHATIC INVOLVEMENT CANCER AND THIS SPANS MEN AND WOMEN AND ALL RACES AND YOU CAN SEE OVER TWO DECADES, THE INCIDENCE IN THE UNITED STATES HAS MORE THAN DOUBLED AND THIS OCCURS IN BOTH MEN AND WOMEN AND THE DATA HERE NOW IN 2015 SUGGESTS THE INCIDENCE RATE IS GREATER THAN 8 PER 100,000 COMPARED TO 4 PER 100,000 IN 1992. DATA FROM 2013, IT IS INDICATED IT WILL BE OVER 42,000 CASES IN THE U.S. AND RESULT IN 30,000 DEATHS. SO THIS IS DATA SHOWING YOU INCIDENCE RATES BASED ON RACE AND YOU CAN SEE THAT THE INCIDENCE RATES OF CANCER AMONGST RACE WAS ACTUALLY HIGHEST AMONGST THE NONWHITE RACE. INCIDENCE RACE IN NONWHITES WAS OF 60 PERCENT COMPARED TO THAT IN WHITES AND YOU CAN ALSO NOTICE THE INCIDENTS HAVE BEEN RISING IN ALL RACIAL GROUPS. IN THE PURPLE LINE ARE THE ASIAN-PACIFIC ISLANDERS, THE BLUE LINE ARE AMERICAN INDIANS AND AMERICAN NATIVES -- SORRY, THE LIGHT BLUE LINE. THE DARK BLUE LINE, HISPANICS, GREEN LINE ARE AFRICAN-AMERICANS AND THE WHITE LINE -- SORRY, THE RED LINE, THE WHITE POPULATION. AND YOU CAN SEE IN THE LAST 12 YEARS, THE INCIDENT RATES HAVE BEEN INCREASING IN ALL RACIAL GROUPS EXCEPT THAT OF ASIAN PACIFIC ISLANDERS WHERE IT SEEMS TO BE DECREASING. NOTABLY IN 2011, THE INCIDENCE OF HCC IS NOW HIGHEST IN HISPANICS, EXCEEDING THAT OF ASIAN-PACIFIC ISLANDERS AND THIS IS LIKELY DUE TO THE RISING INCIDENCE OF NONALCOHOLIC FATTY LIVER DISEASE IN THIS GROUP. SO AS MENTIONED IN THE INTRODUCTION, HIGH FATALITIES IN THIS IS BECAUSE THE SYMPTOMS DO NOT REPRESENT THEMSELVES AND AS A RESULT, MOST PATIENTS PRESENT QUITE LATE IN THE DISEASE. AND WE KNOW CIRRHOSIS IS THE HIGHEST RISK FACTOR FOR HCC REGARDLESS OF THE ETIOLOGY. SO THE QUESTION ARISES SHOULD WE SCREEN PATIENTS IN AN ATTEMPT TO DECREASE THE MORTALITY, BEING IN YOU CAN PICK UP THE DISEASE AT AN EARLIER STAGE, PERHAPS YOU CAN HAVE A BETTER OUTCOME. THE DECISION TO SURVEY A PATIENT IS CONTROVERSIAL AND REALLY& DEPENDS ON THE RISK AND INCIDENCE OF THE HEPATOCELLULAR CARCINOMA, THE LIFE EXPECTANCY, WILLINGNESS TO COMPLY WITH SCREENING AND THE COST. UNFORTUNATELY THERE IS NO DATA, EXPERIENCE DATA OF WHAT IS THE EFFECT AND SO THE ANALYSIS GOES TO COST EFFECTIVE MODELING AND THESE SHOW AN INCIDENCE RATE OF 1.5 PERCENT, IT IS COST EFFECTIVE TO SCREEN FOR HEPATOCELLULAR CARCINOMA. THE ONE CAME AT IS FOR -- CAVEAT IS PATIENTS WITH CHRONIC HEPATITIS B VIRUS, IT IS MUCH LOWER. SO WHAT YOU WILL NOTICE IS THESE ARE MOSTLY ALL OBSERVATIONAL STUDIES INCLUDING 11,000 PATIENTS AND IN GENERAL, WHAT THESE STUDIES SHOW ARE THAT SCREENING IS ASSOCIATED WITH EARLIER DIAGNOSIS RATE, MORE INDIVIDUALS WHO ARE SCREENED RECEIVE CURATIVE THERAPY AND THE SURVIVAL RATE IS BETTER IN THOSE INDIVIDUALS WHO ARE SCREENED COMPARED TO THOSE WHO ARE NOT SCREENED. SO BASED ON THIS DATA, THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES DOES RECOMMEND SCREENING OF INDIVIDUALS WITH CIRRHOSIS FOR HEPATOCARCINOMA. SO WHO ARE THESE INDIVIDUALS? THESE ARE INDIVIDUALS WHOM SURVEILLANCE HAS BEEN SHOWN TO BE BENEFICIAL. ASIAN MALES WITH HEPATITIS B OVER THE AGE, 40, ASIAN FEMALES WITH HEPATITIS B OVER THE AGE OF 50, BOTH AFRICAN AND NORTH AMERICAN BLACKS WITH HEPATITIS B AND ALL B CARRIERS WITH CIRRHOSIS. INDIVIDUALS WITH HEPATITIS C AND CIRRHOSIS ALSO BENEFIT FROM SCREENING AND THEN PATIENTS WITH PRIMARY COLONGITIS, THE BENEFITS ARE UNCERTAIN IN PATIENTS WITH HEPATITIS B IF YOU ARE YOUNGER THAN 40 AS AS A MALE OR YOUNGER THAN 50 IF YOU ARE FEMALE AND THE MOST RECENT DATA SUGGESTS THEY DO NOT BENEFIT FROM SCREENING BECAUSE THE INCIDENCE OF THE HEPATOCARCINOMA CANCER IN THIS GROUP IS PARTICULARLY LOW AND THE NUMBER ONE WOULD NEED TO BY SCREENING BENEFIT PATIENTS IS QUITE HIGH. AND THEN THOSE WITHOUT ALCOHOL-RELATED CIRRHOSIS. SO WHAT STUDY SHOULD BE USED? THE OPTIMAL SCREENING INTERVAL IS NOT DETERMINED BUT BASED ON AVERAGE DOUBLING TIME ARE THE TUMOR, OF APPROXIMATELY SIX MONTHS, THE RECOMMENDED SCREENING INTERVAL IS BETWEEN FOUR TO EIGHT MONTHS. ULTRASOUND IS A MODALITY, 60 TO 80 PERCENT AND SPECIFICITY OF 90% FOR THE DETECTION OF HCC. THE AVAILABILITY OF ULTRASOUND IS REASONABLY AVAILABLE IN THE UNITED STATES AND INEXPENSIVE. THE DOWN SIDE IS IT IS INADEQUATE IN 20 PERCENT OF PATIENTS AND THIS IS DUE TO THE RISING OBESITY IN THE UNITED STATES. THE SENSITIVITY, 60 TO 80 PERCENT AND SPECIFICALLY LESS THAN 90 PERCENT. IT IS WIDELY AVAILABLE AND RELATIVELY INEXPENSIVE BUT THE DOWNSIDE IS THAT APPROXIMATELY 20 PERCENT OF THE TUMORS DO NOT EXPRESS THIS MARKER. SO AS AN ALTERNATIVE, SHARED MARKERS ARE BEING EXPLORED BUT MOST NOT A PROVEN BENEFIT AT THE MOMENT. TWO WITH HCC RISK FACTORS FOR PROGNOSIS AND NOT SURVEILLANCE AND THESE ARE THE INCIDENCES. THESE ARE BOTH APPROVED FOR IDENTIFICATION BUT NOT SURVEILLANCE. OTHER MOLECULE TESTS ARE IN VARIOUS STAGES OF DEVELOPMENT INCLUDING GLYPICAN3, ASSAYS FOR HCC-SPECIFIC DNA MUTATIONS, REGIONS OF DNA, MIRNAS, LNCRNAS AND NATIVE AND POST-TRANSLATIONALLY MODIFIED PROTEINS AND EXOSOMES. AT THE MOMENT, THESE ARE CONSIDERED EX EXPERIMENTAL. SO THE EXPOSURE OF THIS TUMOR TO CT OR MRI FOR DIAGNOSIS. A BIOPSY USED TO BE USED BUT IS NO LONGER IN MOST CASES. IT VARIOUS HOWEVER BY THE FOLLOWING ISSUES. AT LEAST IN THE U.S., MOST RADIOLOGISTS I THINK ARE COMFORTABLE AT READING CT AND MR'S. COST OBVIOUSLY IS A CONCERN, PATIENTS WHO CAN'T GO INTO A MRI BECAUSE THEY ARE KHRAUFT -- CLAUSTROPHOBIC. SO THERE ARE GUIDELINES FOR REPORTING ON CT AND MRIS AND THIS GUIDELINE COMES UNDER THE LIVER IMAGING REPORTING AND DATA STORM SYSTEM OR LIRADS. THIS IS A CATEGORY OR STRATA THAT GIVES THEM THE ABILITY TO DETERMINE WHETHER THEY ARE MALIGNANT OR BENIGN. TO MAKE THIS PROBABILITY ON THE HCC IS THE SIZE OF THE LESION, WHETHER THERE IS ARTERIAL ENHANCEMENT AND THREE OTHER FACTORS, THE WASHOUT, CAPSULE APPEARANCE AND THRESHOLD GROWTH. AND USING THESE CRITERIA, FIVE DIFFERENT CATEGORIES OR STRATA HAVE BEEN ASSIGNED, RANGING FROM ONE TO FIVE. SO PATIENTS WHO HAVE A SCAN INTERPRETED AS LIRADS1 OR 2, ASSOCIATED WITH DEFINITE OR PROBABLE BENIGN LESION AND THESE TYPICALLY DO NOT REQUIRE FURTHER ADDITIONAL FOLLOW UP. EXAMPLES OF THESE WOULD BE A BENIGN CYST OR HEMANGIOMA IN THE LIVER. AN EXAMPLE OF THIS LESION WOULD BE A SOLITAIRE LESION LESS THAN 1 CENTIMETER IN SIZE, NOT SEEN ON SUBSEQUENT VENOUS OR PORTAL PHASE. THE LIRADS4 REGION THE OTHER HAND IS ASSOCIATED WITH BEING A HIGH PROBABILITY HEPATOCARCINOMA AND A LESION THAT IS MORE THAN 2 CENTIMETERS WITH ENHANCEMENT BUT NO WASHOUT AND YOU CAN SEE HERE IN THE ORANGE BOXES WHAT CATEGORIES CONSTITUTE THE LIRADS 4 LESION AND THEN IN THE RED BOXES, A 5 LESION CONSIDERED A DEFINITE HEPATOCELLULAR CARCINOMA AND THE PROBABILITY OF CANCER WITH EACH OF THESE CATEGORIES IS SHOWN AT THE BOTTOM HERE, LIRADS1 AND 2, 0 AND 11 PERCENT, 3 AT 33 PERCENT, 4 AT 80 PERCENT AND A LIRADS 5 IS ALMOST A CERTAIN HCC. SO HOW DOES THIS HELP INFORM OUR DIAGNOSTIC WORKUP? EACH OF THESE CATEGORIES CAN THEN BE USED TO DETERMINE WHAT ADDITIONAL INVESTIGATION NEEDS TO BE DONE. SO A SCAN THAT IS NEGATIVE SHOWS NO LESIONS OR THAT IS NONCATEGORIZABLE FOR LIRAD1 OR 2, THESE PATIENTS DO NOT NEED ANY ADDITIONAL INVESTIGATION AND CAN GO BACK TO ULTRASOUND SURVEILLANCE EVERY SIX TO 12 MONTHS BUT ONE CAVEAT IS THAT INDIVIDUALS WITH THE LIRADS 2 REGION HAVE A SMALL PROBABILITY OF BEING A HEPATOCELLULAR CARCINOMA AND COULD BE REVIEWED IN A PERIOD OF SIX MONTHS. THE LIRADS'3 LESION, THE RECOMMENDATION IS THESE PATIENTS UNDERGO REPEAT DIAGNOSTIC TESTING IN A TIME FRAME OF 3-6 MONTHS. ON THE OTHER HAND, THE LIRADS 4 REGION, THESE PATIENTS ARE PROBABLY BEST MANAGED BY A MULTIDISCIPLINARY TEAM AND DECISIONS ON FURTHER INVESTIGATIONS BASED ON THE OUTCOME OF THAT ASSESSMENT. ON THE OTHER HAND, THESE PATIENTS COULD HAVE A SECOND TEST DONE WITHIN THREE MONTHS AND THEN FURTHER MANAGEMENT BASED ON THE FINDINGS OF THAT TEST. THOSE WITH THE LIRADS 5 REGION HAVE DID HE HAVE MISS HC -- DEFINITELY HAVE HCC AND NO INVESTIGATION NEEDS TO BE DONE. SO THE NEXT STEP, STAGING, JUST LIKE ANY OTHER CANCER BUT IT IS IMPORTANT TO RECOGNIZE THE HEPATOCARCINOMA IS VERY DIFFERENT FROM OTHER CANCERS IN THAT THE PROGNOSIS DEPENDS ON TUMOR BURDEN BUT ALSO ON THE SEVERITY OF THE UNDERLYING LIVER DISEASE AND ALSO ON THE PERFORMANCE STATUS OF THE PATIENT. SO TRADITIONAL STAGING SYSTEMS SUCH AS THE TNM STAGING SYSTEM DO NOT PERFORM AS WELL FOR THE HEPATOCELLULAR CARCINOMA AND AS A RESULT ARE, A NUMBER OF OTHER STAGING SYSTEMS ARE DEVELOPED WHICH I WON'T GO INTO OTHER THAN TO DISCUSS THE ONE THAT IS MOST WIDELY USED WHICH IS THE BARCELONA CLINIC LIVER CANCER SYSTEM AND THIS HAS BEEN DOCUMENTED IN EUROPEAN, ARAB SHAN AND PACIFIC POPULATIONS. AND THE REASON FOR THIS, THE STRATA DEVELOPED RANGING FROM 5 AND THEN 8, COULD FIND WHICH TREATMENT IS APPROPRIATE FOR THE CANCER STAGE. SO THE FIRST STAGE IS DEFINED HERE, A VERY EARLY STAGE, LESIONS THAT ARE SINGLE, LESS THAN 2 CENTIMETERS, UNDERLYING LIVER PORTION AND PERFORMANCE STATUS IS CONSIDERED EXCELLENT. STAGE A IS A SINGLE LESION, UP TO THREE NODULES, AGAIN THESE PATIENTS HAVE A PRESERVED LIVER FUNCTION AND PERFORMANCE STATUS. STAGE B IS INTERMEDIATE STAGE, MULTINODULE TUMOR WITH NORMAL LIVER FUNCTION AND THEN YOU GO TO THE ADVANCED STATUS, STILL WITH A FUNCTION BUT REDUCED PERFORMANCE FUNCTION AND THEN FINALLY STAGE D IS END STAGE LIVER DISEASE AND POOR PERFORMANCE STATUS. AND JUST TO REVIEW QUICKLY, THE POOR PERFORMANCE STATUS, THIS IS THE EASTERN GROUP CRITERIA THAT RANGES ON A SCALE OF 0 TO 5, 5 BEING FULLY ACTIVE AND 0 BEING NONE AND THE VARIOUS CATEGORIES IN BETWEEN. SO IT NOT ONLY INCLUDES AN ASSESSMENT OF TUMOR BURDEN, LIVER DISEASE STATUS AS WELL AS PERFORMANCE STATUS. SO THE REMAINDER OF THE TALK, I AM GOING TO SPEND THE REST OF THE TIME DISCUSSING TREATMENT AND TREATMENT CAN BE QUITE SIMPLY CATEGORIZED AS EITHER CURATIVE OR NONCURATIVE AND CURATIVE TREATMENT AS THE NAME IMPLIES IS APPROACHES TO REMOVE THE TUMOR IN ITS ENTIRETY WITH THE GOAL OF TRYING TO PREVENT POST TREATMENT REPRESENCE AND ALSO TO INCLUDE SURVIVAL OF THE INDIVIDUALS AND THIS CAN BE THROUGH SURGICAL DISSECTION AND THESE OPTIONS. THIS IS MEANT TO SLOW THE PROGRESSION OF THE TUMOR AND THE APPROACHES BEING CONSIDERED HERE ARE TRANSARTERIAL CHEMOEMBOLIZATION AND THE NEXT THREE ITEMS. GIVEN THE COMPLEXITY AND THE MYRIAD OF OPTIONS WE HAVE THAT LIES WITHIN THESE PATIENTS, IS REALLY BEST CONSIDERED BY A MULTIDISCIPLINARY TEAM THAT INCLUDES A HEPATOLOGIST, SURGEON, ONCOLOGIST, INTERVENTION RADIOLOGIST AND PATHOLOGIST AND I THINK MOST CENTERS HAVE MOVED TO THIS MULTIDISCIPLINARY TEAM APPROACH. NOW, WHAT I DISCUSSED HERE ARE REALLY GENERALZATIONS AND WHEN TAKING CARE OF AN INDIVIDUAL PATIENT, IT IS OFTEN A LITTLE BIT MORE DIFFICULT TO DETERMINE WHAT'S THE BEST APPROACH. ALL OF THESE MODALITIES I DISCUSSED HAVE BEEN ASSOCIATED WITH OUTCOMES THAT ARE BETTER THAN DOING NOTHING. THE ONLY ONES THAT ARE CONSIDERED ASIDE FROM THE TRANSPLANT ARE SHOWN HERE. ALL A OF THE OTHER APPROACHES THAT HAVE BEEN TRIED, ALTHOUGH THEY HAVE BEEN SHOWN TO DECREASE TUMOR SIZE AND PERHAPS TUMOR BURDEN HAVE NOT BEEN ASSOCIATED WITH IMPROVED SURVIVAL. SO LET'S DISCUSS THEN THE TREATMENT RECOMMENDATIONS BASED ON THE STAGING CRITERIA AND THIS IS BASED ON THE BARCELONA CLINIC LIVER CANCER STAGE. SO I WILL JUST WALK YOU THROUGH THAT ALGORITHM, IF THEY ARE CANDIDATES, THEN LISSECTION IS THE BEST THERAPY. IF THEY ARE NOT A CANDIDATE, THEN ABLATION IS THE BEST OPTION. FOR THOSE WITH EARLY LIVER DISEASE, THESE PATIENTS DO BEST WITH THE TRANSPLANTATION. ON THE OTHER HAND IF THERE ARE COMOREBIDAL DISEASES, THEN THE TRANSECTION IS THE BEST APPROACH. FOR PATIENTS WITH MORE ADVANCED DISEASE WITH VASCULAR INVASION OR EXTRAHEPATIC SPREAD, SYSTEMIC THERAPY IS RECOMMENDED AND THEN THOSE PATIENTS WITH TERMINAL STAGE DISEASE, IT IS THAT THESE INDIVIDUALS HAVE A LIFE EXPECTANCY AT THREE MONTHS OR LESS. ANY OF THE PATIENTS TREATED WITH THESE MODALITY, EXPECTED OUTCOME IS MORE THAN FIVE YEARS AND THOSE WITH THE DISEASE, RANGES FROM TWO TO FIVE YEARS, ADVANCED STAGE DISEASE, MORE THAN ONE YEAR, THOSE WITH TERMINAL DISEASE, IT IS LESS THAN THREE MONTHS. BUT AS I MENTIONED, THESE ARE SORT OF GENERALIZATIONS AND IN A CLINIC, ONE NEEDS TO TAKE A MORE NUANCED APPROACH. WHAT I WANTED TO INTRODUCE HERE IS ANOTHER CONCEPT AND THAT IS OF SEQUENTIAL APPROACH AND THAT IS IF AN INDIVIDUAL QUALIFIED FOR A PARTICULAR TREATMENT BASED ON THEIR STAGE BUT THEN HAS A DIFFERENT PERFORMANCE STATUS OR MORE ADVANCED DISEASE OR WHILE WAITING FOR A DECISION TO BE MADE ON TREATMENT EXPERIENCES TUMOR PROGRESSION, THEN ONE CAN ALWAYS MOVE SEQUENTIALLY THROUGH THIS TREATMENT ALGORITHM. SO QUITE SIMPLY WHAT THIS MEANS IS THAT INDIVIDUALS WITH EARLY STAGE DISEASE WHO MAY BE CANDIDATES FOR THE ABLATION OR TRANSSECTION CAN SOMETIMES RECEIVE BENEFITS BY MOVING TO THE NEXT STAGE. AND LIKEWISE, THOSE WITH INTERMEDIATE STAGE DISEASE MAY QUALIFY FOR SYSTEMIC THERAPY AND FINALLY THOSE WITH ADVANCED STAGE DISEASE WHO MAY NOT QUALIFY FOR SYSTEMIC THERAPY, THESE INDIVIDUALS MAY BENEFIT FROM PARTICIPATING IN EXPERIMENTAL TRIALS. SO FOR THE REST OF THE TALK, I WOULD LIKE TO FOCUS ON SOME OF THE NUANCES ASSOCIATED WITH MANAGING PATIENTS WITH HEPATOCELLULAR CARCINOMA AND I WILL DEAL WITH EACH OF THESE INDIVIDUALLY. SO FOR PATIENTS WITH VERY EARLY STAGE DISEASE AS I MENTIONED, RESECTION PREFERRED OVER& ABLATION BUT THERE IS STILL SOME CONTROVERSY OVER WHETHER THIS IS THE CASE. WHAT I SHOW YOU HERE IS THE SYSTEMATIC REVIEW OF RESECTION VERSUS ABLATION WITH PATIENTS WITH COMPENSATED CIRRHOSIS AND CARCINOMA. SO THERE HAVE BEEN THREE RANDOMIZED CONTROLLED TRIALS LOOKING AT THIS PARTICULAR PATIENT POPULATION AND WHAT YOU CAN APPRECIATE HERE IS THAT FOR PATIENTS WITH COMPENSATED CIRRHOSIS AND EARLY STAGE HEPATOCELLULAR CARCINOMA, RESECTION IS ASSOCIATED WITH BETTER OVERALL SURVIVAL, BETTER TWO-YEAR STIFLE COMPARED TO PATIENTS WHO ARE TREATED WITH ABLATION. ON THE OTHER HAND, RESECTION IS ASSOCIATED WITH HIGHER COMPLICATED HIGHER COMP -- COMPLICATIONS AND LONGER HOSPITAL STAY. SO THE ARE RECOMMENDATIONS CURRENTLY CONTINUE TO SUPPORT RESECTION OVER ABLATION FOR THIS PARTICULAR POPULATION. NOW GIVEN THE HIGH RECURRENCE RATE IN PATIENTS WHO UNDERGO RESECTION AND THE DATA SUGGESTS THAT UP TO 75 PERCENT OF PEOPLE WHO ARE TREATED WITH RESECTION MIGHT HAVE RECURRENT DISEASE BY YEAR 5, THE QUESTION REMAINS, IS THERE A ROLE FOR THERAPY AFTER RESECTION AND ABLATION AND AGAIN, THERE IS NOT A LOT OF GOOD STUDIES TO INFORM THIS QUESTION. WHAT I SHOW YOU HERE IS A SYSTEMATIC REVIEW THAT HAS LOOKED AT THE THERAPY AFTER RESECTION OR ABLATION AND TOGETHER, THERE HAVE BEEN BE EIGHT RANDOMIZED TRIALS THAT EVALUATED VARIOUS FORMS OF THERAPY INCLUDING CHEMO YO THERAPY, RADIAL THERAPY, TRANSHEPATOCHEMO THEIR AND ESSENTIALLY WHAT ALL OF THESE STUDIES SHOW IS THE OVERALL SURVIVAL IS NOT IMPROVED WITH ADJUTANT V -- ADJUVANT THERAPY SO IT IS NOT RECOMMENDED UNTIL WE HAVE BETTER OPTIONS. SO TURN NOW TO PATIENTS AT THE EARLY STAGE OF THE DISEASE, THERE ARE TWO QUESTIONS HERE THAT ARE CONTROVERSIAL. THE FIRST IS, IS THERE A ROLE FOR BRIDGING THERAPY WHILE WAITING FOR A LIVER TRANSPLANT IN PATIENTS WITH A T2 LESION WHICH FALLS WITHIN THE MILAN CRITERIA. JUST TO REMIND YOU. MILAN CRITERIA EVOLVED TWO DECADES AGO FROM A LANDMARK STUDY IN ITALY AND THIS STUDY DEFINED THE PATIENT POPULATION THAT DID WELL WITH TRANSPLANTATION AND THESE WERE INDIVIDUALS WITH A SINGLE LESION UP TO 5 CENTIMETERS, LESS THAN 3 CENTIMETERS IN SIZE WITHOUT SPREAD OR INVASION. AND PATIENTS WHO MET THIS CRITERIA, THE OUTCOME WAS GENERALLY EXCELLENT. 85 PERCENT IN FOUR YEARS. IN CONTRAST TO THOSE PATIENTS OUTSIDE THE MILAN CRITERIA, THE OUTCOME WAS 50 PERCENT AT FOUR YEARS. SO THE SECOND CONTROVERSIAL QUESTION FOR THIS PATIENT POPULATION IS WHAT ABOUT PATIENTS OUTSIDE OF THAT CRITERIA, THE T3 LESION, SHOULD THEY BE DOWN STAGED WITHIN THE CRATE TEAR? SO I ASK THE QUESTION FIRST AND WHY DO WE CONSIDER THERAPY FOR PATIENTS AWAITING LIVER TRANSPLANTATION WITHIN THE CRITERIA? AND REALLY THE GOAL IS TO MINIMIZE THE PROGRESSION OF THE TUMOR WHILE ON THE TRANSPLANT WAIT LIST AND THIS ALL RELATES TO THE FACT THAT WHEN SOMEONE IS PLACED ON A TRANSPLANT LIST, IT GENERALLY TAKES ANYWHERE FROM, YOU KNOW, THREE TO SIX MONTHS, SOMETIMES LONGER FOR THAT INDIVIDUAL TO GET AN ORGAN AND THIS IS BECAUSE THE NUMBER OF ORGANS THAT ARE DONATED FOR TRANSPLANTATION IS FIXED IN THE U.S., CAPPED AT ABOUT 5 TO 6000 ORGANS ANNUALLY. SO WHAT TYPES OF BRIDGING THERAPY ARE AVAILABLE? TRANSARTERIAL CHEMOEMBOLIZATION OR DAYS, THE Y90 BEADS OR TACE AND ABLATION. AND THE REASON THIS IS SOMEWHAT CONTROVERSIAL BECAUSE THE USE OF THE THERAPY CAN BE ASSOCIATED WITH HELPATIC DECOMPENSATION AND IN REGIONS WHERE THERE ARE SHORT WAIT TIMES, THE THERAPY MAY NOT BE NECESSARY. SO ISSUES BRIDGING WITH THERAPY, THAT IS SHOWN HERE ON THE SLIDE, THEY WERE ALTOGETHER AT 18 TRIALS, HOWEVER MOST OF THEM WERE COHORT OBSERVATIONAL TRIALS AND NOT RANDOMIZED CONTROL TRIALS. THE ONES -- THERE WERE TWO -- SORRY, THREE RANDOMIZED CONTROL TRIALS THAT LOOKED AT BRIDGING THERAPY FOR PATIENTS WHILE AWAITING TRANSPLANT AND WHAT THEY SHOWED, IF YOU LOOK AT THE FIRST TWO ROWS, THAT THERE WAS A TREND IN DECREASED DROPOUT DUE TO THE DISEASE PRO DEPRESSION OR DROPOUT FROM ALL CAUSES IN PATIENTS WHO RECEIVED THE BRIDGING THERAPY. HOWEVER, RECURRENCE WAS NOT DIFFERENT IN PATIENTS WHO RECEIVED THE BRIGING THERAPY AND ARE BASED ON THIS ANALYSIS, EXPERT GUIDELINES RECOMMEND THAT THE BRIDGING THERAPY FOR THE REASON TO PREVENT WAIT LIST DROPOUT OR DISEASE PROGRESSION WHILE AWAITING A TRANSPLANT. SO THIS IS THE PRIMARY REASON WHY WE STILL RECOMMEND BRIDGING THERAPY WHILE AWAITING A TRANSPLANT. WHAT ABOUT THE SECOND QUESTION? OH, OKAY I WILL JUST QUICKLY RUN THROUGH THIS. THIS WAS TO ANSWER THE SECOND QUESTION, WHETHER PATIENTS OUTSIDE MILAN CRITERIA COULD THEN BE TREATED, DOWN STAGED AND SUCCESSFULLY TRANSPLANTED AND BECAUSE TIME IS SHORT, I WILL SAY BASICALLY THE ANSWER IS YES, THE DATA DOES SUPPORT DOWNSTAGING AND TRANSPLANTATION WITH SEVERAL CAVEATS AND THAT IS THE OPTIMAL FORM OF DOWNSTAGING THERAPY IS NOT KNOWN, THE TIME IS NOT KNOWN. THERE ARE NO STANDARD CRITERIA SO DEFINE WHAT THE SUCCESS OF DOWNSTAGING IS AND THE POLICY PREVENTS A PATIENT WITH A CERTAIN LIVER LEVEL FROM THE DOWNSTAGING PROCEDURE BECAUSE OF THE RISK OF TUMOR RECURRENCE IN THIS PARTICULAR PART OF THE POPULATION WITH HIGHER PROTEIN LEVELS. SO WHETHER LOCAL REGIONAL THERAPY IS EFFECTIVE WITH PATIENTS WITH CIRRHOSIS AND AGAIN, THE SHORT ANSWER IS THE ONLY -- SO THE PATIENT POPULATION WE'RE TALKING ABOUT HERE, THOSE INDIVIDUALS WITH A LARGE OR MULTINODULAR TUMOR, 2 OR T3 ARE NOT ESSENTIALLY AVAILABLE FOR THE TRANSPLANTATION. THE FINAL QUESTION IS WHAT IS THE OPTIMAL MANAGEMENT OF PATIENTS WITH HEPATOCARCINOMA WHO HAVE VASCULAR INVASION OR METASTATIC DISEASE? AND HERE THE OPTIONS ARE SYSTEMIC THERAPY, LOCAL REGIONAL THERAPY OR TO DO NOTHING AND CURRENT GUIDANCE RECOMMENDS SYSTEMIC TREATMENT OVER NO TREATMENT. THERE IS NO RECOMMENDATION FOR SYSTEMIC THERAPY OVER LOCAL REGIONAL THERAPY AND NO PREFERRED LOCAL REGIONAL THERAPY AND WHAT I WANT TO QUICKLY SHOW YOU HERE, THAT SINCE 2008, THERE IT ARE A NUMBER OF -- BETTER UNDERSTANDING OF THE CELLULAR PATHWAYS INVOLVED WITH THE PATHOGENESIS OF THE HEPATOCARCINOMA. THERE ARE A NUMBER OF SMALL MOLECULE K -- KINASE MOLECULES THAT HAVE BEEN SUCCESSFUL WITH PATIENTS WITH LIVER CANCER. THESE ARE THE ONLY ONES ASSOCIATED WITH SURVIVAL BUT I WOULD POINT OUT HERE IF YOU LOOK AT THE LAST COLUMN -- SORRY, SECOND TO THE LAST COLUMN, SURVIVAL IS ASSESSED BASED ON MONTHS. WE'RE TALKING ABOUT A DIFFERENCE IN OUTCOME HERE OF THREE MONTHS BETWEEN THOSE WHO WERE TREATED VERSUS THOSE WHO WERE NOT TREATED. BUT THERE IS PROMISE ON THE HORIZON. THERE ARE A NUMBER OF NOVEL AGENTS THAT ARE BEING EVALUATED NOW FOR HEPATOCARCINOMA INCLUDING IMMUNE CHECKPOINT INHIBITORS, CTL4, PD1 AND LIGAND TO PD1, THE KINASE INHIBITOR AND IMMUNOTHERAPY. SO THESE ARE MY LAST SLIDES AND I WOULD BE REMISS IF I DIDN'T TALK ABOUT REVEX. WHEN I INTRODUCED THIS IN THE INTRODUCTION, THIS IS SHOWING IMMUNIZATION AGAINST HEPATITIS B ASSOCIATED WITH DRAMATIC REDUCTION IN MORTALITY FROM PATIENTS WITH CHRONIC HEPATITIS B AND THIS IS DATA FROM TAIWAN WHICH WAS THE FIRST COUNTRY TO INTRODUCE HEPATITIS B VACCINATION IN THE WORLD BECAUSE OF THE HIGH RATES OF HEPATOCELLULAR CARCINOMA IN THAT COUNTRY. SO FOCUS ON THE RIGHT PANEL AND WHAT I WILL SHOW YOU HERE ARE THE RATES IN MALES AND FEMALES PRIOR TO THE INTRODUCTION OF IMMUNIZATION PROGRAMS. AND YOU CAN SEE FOLLOWING THE INTRODUCTION OF THE IMMUNIZATION PROGRAM IN 1984, THERE WAS MORE THAN A 90 PERCENT REDUCTION IN HCC RATES IN BOTH MEN AND WOMEN FOLLOWING THE HPB VACCINATION SO THIS WAS ACTUALLY THE FIRST VACCINE THAT COULD PREVENT A TUMOR FROM OCCURRING. AND IF THERE IS NOTHING ELSE YOU TAKE FROM THIS TALK, WHEN YOU LEAVE THIS ROOM, THIS IS THE ONE THING I WOULD LIKE TO IMPRESS UPON YOU. VACCINATION HAS BEEN IN THE NEWS RECENTLY BECAUSE OF THE MEASLES OUTBREAK. THIS IS A SAFE VACCINE. IT IS EFFECTIVE AT PREVENTING HEPATOCELLULAR CARCINOMA AND I WOULD ENCOURAGE THOSE OF YOU WHO PRACTICE MEDICINE TO RECOMMEND THIS FOR ALL YOUR PATIENTS. IT DOES WORK. AND THEN FINALLY, WITH THE DEVELOPMENT OF NOVEL, SAFE HIGHLY EFFECTIVE ANTIVIRAL THERAPY FOR HEPATITIS C NOW, WE CAN ACHIEVE VIRALOGIC CLEARANCE IN MORE THAN 95 PERCENT OF PATIENTS AND THERE IS NOW SOME EMERGING DATA THAT SUGGEST THE BIOLOGIC TREATMENT WITH THE ANTIVIRAL AGES IS ASSOCIATED WITH THE HEPATOCELLULAR CARCINOMA. THE ONE PATIENT SHOWN IN BLUE HAD A 76 PERCENT REDUCTION IN CANCER RATES COMPARED TO THOSE WHO DID NOT ACHIEVE THIS OVER A PERIOD OF 20 MACHINES SO IT IS HOPED THAT WITH MORE WIDESPREAD OF THESE AGENTS AND TREATMENT OF PEOPLE BEFORE THEY DEVELOP THE CANCER, A LOWER INCIDENCE OF HELP CELLULAR CARCINOMA. SO IN THIS COUNTRY, THIS IS THE CAUSE HERE AND THE VIRUS IS ASSOCIATED WITH THE MAJORITY OF ALL CANCERS SO IF WE CAN PREVENT THIS, WE CAN HAVE A DRAMATIC EFFECT ON HCC. BETTER BIOMARKERS FOR HCC ARE NEEDED AND DESPITE ADVANCES IN THERAPY, MORTALITY REMAINS UNACCEPTABLY HIGH AND WE CLEARLY NEED BETTER ADJUVANT THERAPY, ASSOCIATED WITH REDUCING THE RATES IN ALL PATIENTS SO THANKS SO MUCH FOR YOUR ATTENTION AND I AM HAPPY TO TAKE ANY QUESTIONS. [APPLAUSE] >> WE HAVE TIME FOR A FEW QUESTIONS SO PLEASE GO TO THE MICROPHONE. SO YOU EMPHASIZED CIRRHOSIS. WHAT ABOUT PATIENTS WHO DON'T HAVE CIRRHOSIS? OR WE DON'T TALK ABOUT THAT ANYMORE? >> WELL, THANKFULLY THAT IS ACTUALLY A RARE OCCURRENCE, CIRRHOSIS -- SORRY, HCC OCCURRING IN THE ABSENCE OF CIRRHOSIS. MOST CASES OF HCC DO OCCUR IN THE PRESENCE OF CIRRHOSIS AND AS YOU MENTIONED, AT THE BEGINNING OF YOUR TALK, IF YOU FIND PLACES OF CANCER APPEARING IN THE ABSENCE OF CIRRHOSIS, THOSE ARE WORTH TALKING ABOUT. >> THANK YOU SO MY QUESTION IS WHY IS HPV STILL ENDEMIC SO LONG AFTER THE VACCINE HAS BEEN INTRODUCED AND WHAT DO YOU THINK THE IMPACT WILL BE FROM THE RESULTING FEAR OF VACCINES IN THAT AREA? >> YES, THANK YOU FOR THAT QUESTION. IT IS A GREAT QUESTION. IT IS ONE THAT HAS PERPLEXED US FOR A LONG TIME BECAUSE WE HAVE HAD AN EFFECTIVE VACCINE THAT HAS BEEN AVAILABLE SINCE THE EARLY 80s. INITIALLY IT WAS A PLASMA-DERIVED VACCINE, NOW A RECOMBINANT VACCINE. THAT VACCINE HAS TO BE GIVEN IN THREE DOSES, AT BIRTH, ONE MONTH AFTER BIRTH AND SIX MONTHS AFTER BIRTH. WE NOW HAVE A COMBINATION VACCINE THAT IS TOGETHER WITH HEPATITIS A AND HEPATITIS B SO YOU CAN GET BOTH AT THE SAME TIME AND THERE IS NOW A NEWER VACCINE THAT IS ADMINISTERED WITH CPG THAT IS MORE IMMUNOGENIC AND YOU ONLY HAVE TO GET TWO DOSES. THIS VACCINE IS ONLY APPROVED FOR ADULT AND NOT IN CHILDREN. SO YOUR QUESTION WAS WHY IS IT THAT WE HAVE AN EFFECTIVE VACCINE THAT WE'RE STILL SEEING INCREASES IN CANCER RATES AND THAT IS BECAUSE WE HAVE FAILED AS A MEDICAL COMMUNITY TO VACCINATE OUR PATIENTS. SO DESPITE RECOMMENDATIONS FROM WHO AND OTHER GLOBAL ORGANIZATIONS, VACCINE UPTAKE IS STILL LOW GLOBALLY. SO THE WHO HAS SET A RECOMMENDATION TO HAVE MORE THAN 90 PERCENT UPTAKE OF FIRST DOSE HPV VACCINE AND GLOBALLY, THIS IS AROUND 41 PERCENT. SO YOU CAN SEE THAT WE HAVE A LONG WAYS TO GO. HERE IN THE UNITED STATES, IT IS ONLY 80 PERCENT FIRST DOSE VACCINE AND THE IDEA IS TO HAVE THIS VACCINE ADMINISTERED WITHIN 24 HOURS OF BIRTH. UNFORTUNATELY, THERE ARE AREAS OF THE WORLD CHA HAVE THE GREATEST BURDEN OF CHRONIC HEPATITIS -- SORRY, OF CANCER, THESE ARE AREAS OF THE WORLD ASSOCIATED ALSO WITH A HIGH PREVALENCE OF HEPATITIS B. THEY ARE ALSO AREAS OF THE WORLD WHERE IT IS DIFFICULT TO GET VACCINE BECAUSE OF STORAGE AND SO FORTH. SO WE WOULD REALLY NEED TO HAVE A MORE EFFECTIVE VACCINE FOR THIS TO BEGIN TO SEE A DECLINE INPV-RELATED HCC RATES. THE OTHER THING IS MANY INDIVIDUALS DECLINED TO RECEIVE THE VACCINE FOR RELIGIOUS, CULTURAL OR OTHER BELIEFS AND THIS IS PARTICULARLY SO IN AREAS OF THE WORLD WHERE HPV IS VERY PREVALENT SLUDGE AS NIGERIA, INDONESIA, WHERE UPTAKE OF THE VACCINE IS EXCEEDINGLY LOW. SO THIS IS WHY PREVALENCE OF HCC IS STILL HIGH. THE OTHER OF COURSE IS THE OTHER DISEASES ASSOCIATED WITH LIVER CANCER THAT WE DON'T HAVE VACCINATIONS FOR SUCH AS HEPATITIS C AND NOW NONALCOHOLIC FATTY LIVER DISEASE. >> OKAY, MARC, THANK YOU, WE WILL HAVE MORE TIME FOR QUESTIONS AFTERWARDS. >> I AM HERE TO TALK ABOUT LIVER CANCER, A LEADING CAUSE OF CANCER DEATHS WORLDWIDE SO A LARGE PROPORTION OF LIVER CANCER, HEPATOCARCINOMA AND MAINLY ATTRIBUTABLE TO VIRAL INFECTION. PATIENTS HAVE A RELATIVELY POOR OUTCOME AND DUE TO LATE DISEASE STAGES AT PRESENTATION. SO WE HAVE AN URGENT NEED FOR ACCURATE METHODS TO DIAGNOSE LIVER CANCER AND PREDICT OUTCOME AND IDENTIFY NOVEL THERAPUTIC OPTIONS. SO AS WAS MENTIONED, LIVER CANCER IN THE U.S., THIS IS A CURRENT STATUS IN 2019, ABOUT 42,000 CASES ARE ESTIMATED THIS YEAR WITH ABOUT 31,000 ESTIMATED DEATHS THIS YEAR ACROSS BOTH SEXES. IN TERMS OF DEATHS, FIFTH LEADING IN MEN AND SIXTH LEADING AMONG WOMEN. LIVER CANCER IS RISING IN THE UNITED STATES AND THIS IS THE STATE WITH AGE ADJUSTED HCC RATES FROM 2003 TO 2012 AND WHAT YOU CAN APPRECIATE HERE IS THE COLOR CHANGE AS WE GO TO A DARKER BROWN IN 2012 SHOWING A VERY HIGH INCIDENCE OF THIS CANCER AND IT HAS ESSENTIALLY DOUBLED IN THE LAST TWO DECADES. ON THE BOTTOM, MORTALITY RATES OVER TIME FROM 1980 TO 2014, THE STUDY RISE NATIONALLY AND ACROSS COUNTIES IN THE U.S. AND AGAIN, ONE OF THE TOP CANCERS IN TERMS OF MORTALITY AMONG MEN AND WOMEN IN THE U.S. IN THE WORLD, LIVER CANCER IS ONE OF THE LEADING CAUSES OF DEATH. HERE AS SHOWN PREVIOUSLY, MALES ON THE LEFT, FEMALES ON THE RIGHT, A VERY PROMINENT CANCER TYPE IN ASIA AND SUBSAHARAN AFRICA IN TERMS OF INCIDENCE AND MORTALITY AND INCREASING IN MORE WESTERNIZED POPULATIONS. SO LIVER CANCER PROFESSES FROM THE NORMAL LIVER TO CIRRHOSIS TO HEPATOCELLULAR CARCINOMA, LIVER CANCER, TO MESS -- MESTACES. THIS CANCER IS ALSO VERY HETEROGENEOUS STEMMING AND A NUMBER OF FACTORS, LIKE AGE AND GENDER AND RACE, PARASITE FACTORS, SMOKING, ALCOHOL, AND THESE CAN ELICIT DIFFERENT MECHANISMS THAT CAN INITIAE MALIGNANT M PERSON NATION AND THAT IS DEPICTED HERE IN THE ARTIST RENDITION. SO WHAT ARE SOME OF THE RESEARCH DIRECTIONS WE ARE PURSUING AND ONES I WILL DISCUSS TODAY? THE FIRST ARE GENOMIC APPLICATIONS THAT WE'RE UTILIZING TO UNDERSTAND WITH LIVER CANCER AT THE INTER AND INTRA RESPECT OF THE DISEASE, THE POTENTIAL TREATMENT WITH THERAPY AND THE LAST RESEARCH THING I WILL TALK ABOUT IS THE HEALTH OF THE DECEMBER. SO HOW DO WE TAKE THIS VERY HETEROGENEOUS DISEASE, UTILIZE THAT IN THE LABORATORY TO TAKE THE MIXTURE AND IDENTIFY MORE PARTICULAR SUBTYPES THAT WE CAN UNDERSTAND MORE DISCREETLY ABOUT WHAT THE MOLECULAR SUBTITLEING OF THESE TYPES ARE AND THAT MIGHT HELP US FIND SPECIFIC BIOMARKERS FOR EACH SUBTYPE AND SPECIFIC TARGETS FOR EACH SUBTYPE. SO THE WAY WE THOUGHT ABOUT DOING THIS IS BUILDING LIVER CANCER ECOSYSTEMS WITH INTEGRATE SYSTEMS BIOLOGY AND HOPEFULLY THIS WILL BE UTILIZED TO IMPROVE PATIENT OUTCOME. SO THE FIRST STEP IS TO PROVIDE BIOBANGS TO INCLUDE TISSUE, NONTISSUE, BLOOD, URINE, ET CETERA, COMBINED WITH CLINICAL INFORMATION. THIS IS THEN MIXED WITH A NUMBER OF VARIETIES FOR GROUP STATUS INCLUDING THESE ITEMS. WE COMBINE THE CLINICAL WITH HIST AND PATHOLOGICAL INFORMATION AND HOPE TO INCLUDE MORE GROUPS BY THIS DATA. THIS WOULD HOPEFULLY ENABLE US TO USE BIOMARKERS TO TALK ABOUT IMPACT ON LIFE AND SURVIVAL. SO TO GIVE YOU A FEW EXAMPLES OF HOW WE HAVE UTILIZED THIS STRATEGY IN THE LABORATORY, ONE OF THE QUESTIONS THAT WE LOOKED AT EARLIER ON IN THE LAB IS DEGREE OF METASTESIS AND WHAT IS THE DIFFERENT BETWEEN THE PATIENTS WHO HAVE IT VERSUS THOSE WHO DO NOT SO WE UTILIZED THE COHORT BETWEEN THOSE PATIENTS WHO HAVE METASTESIS VERSUS THOSE WHO DO NOT AND WE WERE ABLE TO TKAEUFRPBT UNITE PATIENTS BASED ON THE EXPRESSION OF 153 GENES AND PATIENTS WERE EITHER PREDICTED TO HAVE GOOD OR POOR SURVIVAL BASED ON THE EXPRESSION OF THESE GENES. WE HAVE SINCE VALIDATED THE SIGNATURE WITH ONE COHORT, STRAT OCCASION OF PATIENTS BASED ON GENUS EXPRESSION AND COMBINED THAT WITH CLINICAL FACTORS SUCH AS ALPHA FEET TALL PROTEIN -- FETAL PROTEIN AND WE CAN UTILIZE THE DATA IN CONCERT WITH STAGING DATA TO DEFINE PATIENT GROUPS AND EVEN AT THE EARLY STAGES, PATIENTS ARE SPOUT THOUGH HAVE BETTER OUTCOME BUT USING OUR GENE SIGNATURE, WE STILL MANAGE TO FIND A GROUP OF PATIENTS WITH MORE OUTCOME SO THIS IS INTERESTING FOR US TRYING TO FORM BIOMARKERS RELATED TO METASTASIS AND POOR OUTCOME. IN ADDITION TO THE GENE EXPRESSION, WE HAVE USED MICRORNAS TO COMPARE PATIENTS WITH METASTASIS, THE REGULATED CODING, DEREGULATED GENES, ABLE TO SEPARATE METASTATIC FROM THE NONMETASTATIC INDIVIDUALS AND THE BIOMARKERS RELATED TO PATIENT OUTSOME -- OUTCOME. SO WE HAVE ALSO USED GENE SIGNATURES TO UNDERSTAND A BIT ABOUT THE ORIGINS OF THE LIVER CANCER IN TERMS OF THEIR LINEAGE SO WE CAN GO FROM COLANGEOCYTES OR OTHERS CANCER. WE HAVE UTILIZED GENE EXPRESSION TO IDENTIFY MOLECULAR SUBTYPES THAT RELATES TO DIFFERENTIATED FORMS OF LIVER DISEASE OR THE OTHER TYPES, THE MORE AGGRESSIVE FORMS OF THE DISEASE AND THEY ARE ASSOCIATED WITH POOR SURVIVAL. WE CAN INTERROGATE WHAT THOSE GENES ARE AND THE PATHWAYS THEY ARE INVOLVED IN TO FIND OUT WHAT THE HE COULD TPHO*EDZ OF THOSE SIGNALING MECHANISMS ARE AND THOSE ARE POTENTIALLY MARKERS OF THE POPULATION THAT CAN BE EITHER USED AS BIO MARKERS OR TARGETS FOR FUTURE THERAPY IT. MORE RECENTLY, WE HAVE USED TRANSCRIPTOMICS TO UNDERSTAND THE DIFFERENCES OR SIMILARITIES BETWEEN TWO DIFFERENT TYPES OF LIVER CANCER. SO GENE EXPRESSION METHODOLOGY WAS APPLIED TO 62 PATIENTS WITH HEPATOCELLULAR CARCINOMA AND YOU CAN SEE WE CAN DIVIDE THE PATIENTS WITH THREE CATEGORIES OR SUBGROUPS. IN COLANGEO CANCER, WE CAN ALSO DIVIDE THESE PATIENTS IN SUBGROUPS. THIS WAS DONE BY A BIOFRENETIC MAPPING AND WHAT YOU CAN FOCUS ON HERE ARE THE RED SQUARES WHICH ARE THE SIMILAR SUBGROUPS WITH SIGNIFICANT T-VALUES AND THESE PARTICULAR SUBGROUPS IN COMMON IN THESE TWO CANCERS ALSO SHOW COMMONALITY IN THEIR DISTINCTION OF PATIENT SUBGROUPS. SO THE C1 GROUP THAT IS PRESENT IN COLANGEO CARCINOMA HAVE POOR OUTCOMES AS THE OTHER PATIENT GROUPS. SO WHAT THIS IS TELLING US IS WHAT WE USUALLY THINK OF TWO DIFFERENT DISCREET TYPES OF LIVER CANCER AND ARE TREATED WITH AT THE CLINIC, PATIENTS WITH ONE TIME OR ANOTHER TYPE HAVE SIGNALING MECHANISMS AND COULD BE POTENTIALLY TREATED IN SIMILAR FASHION. SO THUS FAR I HAVE MENTIONED STUDIES WHERE WE HAVE LOOKED AT ONE PATIENT TO ANOTHER, THIS IS CALLED INTERHETEROGENIITY. THE OTHER TYPE IS I NTRAHETEROGENEITY. SO WE ISOLATE THE DNA AND RNA AND PERFORM SEQUENCING ANALYSIS AND THIS CAN TELL US MANY DIFFERENT THINGS. WE CAN COMBINE IT WITH OTHER TYPES OF OMICS DATA AND LEARN ABOUT CONSUMER CELL COMMUNITIES, CELLULAR HIERARCHY, WHAT IS COLLECTIVE BEHAVIOR OF THESE CELLS, HOW ARE THEY REGULATED, WHAT ARE SOME OF THE DRIVING MECHANISMS, ARE THEY COMMON OR DIFFERENT AND PERHAPS WHAT ARE THE MECHANISMS TO TUMOR RESISTANCE THERAPY GIVEN A CERTAIN CELL POPULATION IN ABUNDANCE VERSUS ANOTHER? SO TWO EXAMPLES OF THIS WHERE WE HAVE LOOKED AT HCC, THESE ARE THREE REPRESENTATIONS OF HCC CELLS WHERE WE LOOK AT TWO-DIMENSIONAL CULTURING OF CELLS IN MODELS, THIS IS A WAY OF LOOKING AT A THREE-DIMENSIONAL STRUCTURE WITHIN THE PHYSICAL BODY. WE HAVE MARKED THE VARIETY WITH STEM CELL MARKERS, MARKERS FOR AGGRESSIVE DISEASE AND THEY ARE ALL HIGHLIGHTED WITH DIFFERENT FLUORESCENT MARKERS SO WE CAN SEE IT UPON IMAGING AND YOU SEE THE COMPLEXITY IT OF A SINGLE ORGANI. WE CAN USE SEQUENCING TO TRY TO CAPTURE WHAT IS HAPPENING IN THIS PARTICULAR ORGANOID AND DIFFERENTIATE CELLS THAT ARE EXPRESSING ONE MARKER HERE OR EXPRESSING ALL OF THE MARKERS AND YOU CAN SEE THESE CELLS ARE SEPARATING FROM ONE ANOTHER BASED ON THEIR TYPES OF SIGNALING IN THE DIFFERENT CELLS AND DIFFERENT REGIONS. WE CAN ALSO LOOK AT CORE BIOPSIES IN HCC, WE CAN PERFORM SINGLE CELL SEQUENCING FOLLOWED BY COMPUTATIONAL ANALYSIS AND HERE SHOW DIFFERENT PATIENTS WITH PRIMARY LIVER CANCER AND THE DIFFERENCES AND SINGLE CELLS THAT HAVE BEEN ISOLATED FROM THOSE INDIVIDUALS AND WE CAN THEN GO ON TO STUDY GENE EXPRESSION ALTERATIONS THAT ARE OCCURRING IN THIS PARTICULAR PATIENT VERSUS THAT PARTICULAR PATIENT. SO WE HAVE USED TRANSCRIPTONE-BASED METHODS TO MOLECULARLY CLASSIFY HCC AND WE HAVE DONE THIS AND MANY OTHER LABS HAVE DONE THIS ACROSS THE WORLD AND THIS IS A COMPILATION OF SOME OF THEM. IT IS STILL A VERY COME LEAKS SYSTEM TO ASSESS. WE CAN TAKE THE DATA WE FOUND FROM MANY LABS AND GROUP PATIENTS FROM LESS AGGRESSIVE AND MORE AGGRESSIVE HCC BUT THERE ARE MANY MARKERS BEING ALTERED SO WE HAVE MUCH MORE WORK TO DETERMINE WHO ARE THE DRIVING NODES IN ONE TYPE OF HCC VERSUS ANOTHER. SO THIS IS ONGOING WORK. SO IN ADDITION TO GENE EXPRESSION, I MENTIONED THOSE LEVELS OF OMICS WE CAN CONSIDER, ONE OF THE MORE RECENT OMICS WE HAVE BEEN CONDUCTING IN THE LABORATORY IS AN ASSESSMENT OF ALL THE CHANGES IN METABOLIC PATHWAYS OCCURRING IN THE BODY AND THESE ARE VERY GOOD MARKERS OF A PARTICULAR CELLULAR PHENO TYPE BECAUSE THEY ARE THE END RESULT OF ALL OF THESE PATHWAYS SO THEY ARE BEING DISREGULATED. IT IS A VERY COMPLEX SYSTEM AS YOU CAN SEE AND MANY COFACTORS AND ROUND-ABOUTS AND MANY DIFFERENT BIOCHEMICAL SPECIES. BUT WE HAVE PLATFORMS THAT ARE VERY WELL DEVELOPED AND SPECIALIZED TO LOOK AT METABOLIC PATHWAYS AND SO WE HAVE DONE SO. HERE WE ARE LOOKING AT A SET OF METABOLIC CHANGE ON THE X AXIS AND WE CAN USE THAT TO BUNDLE THE REACTION IN LIVER PATIENTS. WHAT WE CAN SEE IS THAT THESE ARE HIGHLY ABUNDANT IN THIS SUBTYPE BUT LESS ABUNDANT IN THIS TYPE. SO METABOLIC LEVELS ARE ALSO DIFFERENT BETWEEN GROUPS OF PATIENTS THAT HAVE HCC. AND AGAIN, AS I HAD SHOWN WITH THE GENE LEVELS, THE METABOLIC ABUNDANCE CAN ALSO DISCRIMINATE PATIENTS WHO A SURVIVAL-BASED SUBGROUP WHERE THIS PARTICULAR GROUP OF PATIENTS HAVE THE WORST OUTCOME. WE CANNOT ONLY LOOK AT METABOLIC GENES IN TISSUE BUT ALSO IN PRODUCT AND BLOOD SERUM AND THIS IS A MUCH BETTER WAY TO DIFFERENTIATE A BIOMARKER. SO WHAT IS HAPPENING IN THE CIRCULATION NEEDS TO BE A REPRESENTATION OF WHAT IS HAPPENING AT THE TUMOR SITE AT LEAST IN TERMS OF THESE PARTICULAR METOLYTS. SO WHICH ONES ARE SPECIFICALLY BEING ALTERED? THE C1 PATIENTS HAVE A VERY POOR OUTCOME, C2 PATIENTS HAVE A BETTER OUTCOME AND WE CAN SEE HERE THAT METABOLITES CAN DIFFERENTIATE THIS POOR OUTCOME GROUP VERSUS THE GOOD OUTCOME GROUP AND YOU LOOK AT WHAT THEY ARE, MANY BELONG TO A DEOXYCOLATE SPECIES AND AND IN THE BETTER SURVIVAL RATE, THESE ARE HIGH LIE ELEVATED, MORE ABUNDANT THAN IN THE POOR SURVIVAL GROUP. AND THIS HAS RECENTLY BEEN SHOWN IN PARALLEL OR REPLICATED IN TIM GRATTON'S GROUP HERE AT NIH WHERE HE HAS SHOWN THAT THE METABOLITES CAN REGULATE T-CELLS AND THIS IS ALL MODERATE LATE THROUGH THE GUT MICROBIOME, MODIFYING THE BIOACID POOL IN THE BODY MODULATING LIVER CANCER SO THIS IS A NICE CORRELATION FROM THE MOUSE MODEL SYSTEM TO THE HUMAN DATA I SHOWED YOU IN THE PREVIOUS SLIDE. WE CAN ALSO USE METABOLIC ABUNDANCE TO UNDERSTAND WHETHER THEY CAN BE MARKERS OF JUST TUMORS THEMSELVES AND HERE WE ARE SHOWING A SERIES OF METOBOLITES THAT CAN HIGHLY CLASSIFY NONTISSUE SPECIMENS AND SPECIFIC TISSUE SPECIMENS AND WE CAN ASK THIS FER PHENO TYPES OF THE HCC SO WE LOOKED AT THE STEM LIKE HCC VERSUS THE MORE DIFFERENTIATED HCC AND SPECIALLY THE ABUNDANCE OF METABOLITE IN THE DIFFERENTIATED HCC. SO I HAVE SHOWN YOU THE POTENTIAL MARKERS AND HOW WE CAN UTILIZE THAT TO SUB-TYPE PATIENTS AND RELATE THOSE SUBTYPES TO PATIENT OUTCOMES. NEXT I WOULD LIKE TO MOVE TO A NEW PHENO TYPE SO AS WAS MENTIONED, FOR LIVER CANCER, WE NOT ONLY DEAL WITH THE ACTUAL TUMOR AND LIVER ITSELF BUT THE ACTUAL FUNCTION OF THE ORGAN. SO WHAT IS HAPPENING IN THE TUMOR MICROENVIRONMENT UNDER, FOR EXAMPLE, , CIRROTIC CONDITIONS. SO IN THIS STUDY, WE LOOKED AT METS METASTATIC PATIENT VERSUS THE NONMETASTATIC PATIENTS AND LOOKED AT THE PHENO TYPES AND THOSE THAT HAVE METASTATIC DIFFERENCES HAVE A VERY SPECIFIC LOOK TO GENE IMPRESSION. WE CAN USE OTHER METHODS TRYING TO REDUCE THE SIGNIFICANT SO THAT WE DON'T HAVE AS MANY GENES TO LOOK AT AND HERE WE FOUND THAT IF WE DO THAT, WE CAN LOOK SPECIALLY AT CYTOKINE LEVELS IN A SPECIFIC LEVEL CALLED COLONY MACRO 1 WHICH IS FOUND IN PATIENTS WITH METASTASIS VERSUS THOSE WHERE IT IS NOT AND AGAIN, THIS IS THE OUTFLOW IN TERMS OF PATIENT RECURRENCE. SO IN ADDITION TO LOOKING AT THE SPECIFIC GENES THAT ARE BEING EXPRESSED, WE CAN ALSO TRY TO LOOK AT THE POPULATIONS OF IMMUNE CELLS BEING DISREGULATED AND WE CAN DO THIS FROM BIOSPLENATIC PURPOSES, LOOKING AT THE ONE GROUP WITH THE BETTER OUTCOME, WE CAN COMPARE GENE EXPRESSION ASSOCIATED WITH CERTAIN CELLS, B-CELLS, T-CELLS, MACRO CELLS, ET CETERA. SPECIFICALLY WHAT WE FOUND HERE WAS AN ALTERATION OF LEUKOCYTE POPULATIONS, CD 4 AND CD8 CELLS THAT WERE HIGHLY ALTERED IN PATIENTS WHO HAVE A BETTER OUTCOME. IF WE LOOK SPECIFICALLY AT THESE, WE SEE THE T-CELLS ARE ASSOCIATED WITH A HIGHER LEVEL IN THE C2 GROUP VERSUS THE C1 GROUP WHEREAS THE ANTIINFLAMMATORY T-CELLS ARE MORE ABUNDANT IN THIS GROUP. SO THERE ARE LEUKOCYTE POPULATIONS IN PARTICULAR SUBTYPES OF HCC. WE CAN ALSO DO THIS AT THE SINGLE CELL LEVEL SO TAKE BIOPSY SPECIMENS TO ASSOCIATE THEM BUT INSTEAD OF LOOKING AT THE TUMOR CELLS, WE CAN LOOK AT THE NONMALIGNANT CELLS AND EXPRESSION. SO HERE WE CAN DIFFERENTIATE THESE FROM A PARTICULAR SPECIMEN AND THEN GO LOOK AT THE EXPRESSION OF THE INDIVIDUAL POPULATION FOR CELLS WITHIN A MICROENVIRONMENT. SO WE KNOW POPULATIONS ARE BEING DISREGULATED IN HCC AND MANY OTHER CANCER TYPES AND WE HAVE HEARD ABOUT IMMUNOTHERAPY IN PAST YEARS AND IT HAS BEEN APPLIED TO LIVER CANCER BY A VARIETY OF DIFFERENT METHODS AS BRIEFLY DISCUSSED BY MARK IN THE PREVIOUS TALK. SOME PATIENTS RESPOND AND SOME PATIENTS DO NOT. AND WE DON'T UNDERSTAND WHY THAT IS. SO IN MULTIPLE DIFFERENT METHODS THAT HAVE BEEN TRIED, WE HAVE GROUPS O PATIENTS THAT ARE RESPONDING TO THIS TREATMENT. OTHERS DO NOT. SO RECENTLY WE HAVE INITIATED A LIVER CANCER SHOP STUDY WHERE WE'RE TRYING TO UNDERSTAND WHY PARTICULAR SETS OF PATIENTS RESPOND TO THE THERAPEUTIC APPROACH AND THE NCI IS COLLABORATING WITH CLINICAL SITES IN AFTERNOON DIFFERENT REGIONS ACROSS THE U.S. WHERE WE ARE LOOKING AT LIVER CANCER PATIENTS BEING TREATED WITH AMINO -- IMMUNOTHERAPY AND THEN CORRELATING THE DATA. WE'RE HOPING TO USE THAT INFORMATION TO STRATIFY PATIENTS TO BE ABLE TO EXPLAIN WHY SOME PATIENTS RESPOND AND OTHERS DON'T AND THIS WILL LEAD HOPEFULLY TO MARKERS THAT CAN BE RELATED WITH NEW THERAPY AND FORM NEW CLINICAL TRIALS SO THIS IS A NEW AND ONGOING STUDY. LASTLY I WOULD LIKE TO DISCUSS THE HOPE AND DISPARITY IN THIS DISEASE. WE HAVE LEARNED A LITTLE BIT ABOUT THIS IN THE LABORATORY. AS MENTIONED BEFORE, THIS IS PREDOMINANTLY A MALE DISEASE AT ABOUT A 3 TO 1 RATIO ACROSS ALL POPULATIONS IN THE WORLD AND SEVERAL YEARS AGO WE LOOKED AT WHAT ARE THE DIFFERENCES BETWEEN MALES AND FEMALES THAT HAVE HEPATOCELLULAR CARCINOMA AND WE ASK THIS AT BOTH THE GENE EXPRESSION LEVEL AS WELL AS THE MICRORNA LEVEL AND WHAT WE FOUND IS THERE WERE A SERIES OF GENES THAT COULD DIFFERENTIATE PATIENTS WITH ONE GENDER VERSUS ANOTHER AND IF WE INTEGRATED THAT INFORMATION AT MICRORNA LEVELS, WE LOOK AT THESE ITEMS. MORE INTERESTINGLY, THOSE PATIENTS WITH LOW LEVELS ACTUALLY RESPOND BETTER TO INTERPHERON TREATMENT AND THAT IS SHOWN HERE WHERE THE LOW LEVELS DO BETTER WHEN TREATED WITH INTERPHERON. AND HERE THE LOW LEVELS ARE HERE AND THE HIGH LEVELS DON'T SHOW ANY DISCREPANCY. SO WE'RE USING IT AS A COMPANION DIAGNOSTIC TO INFORM WHETHER PATIENTS CAN BE TREATED WITH INTERPHERON AND THIS IS IN CLINICAL TRIALS CURRENTLY SO WE'RE AWAITING RESULTS FROM THIS STUDY. WE HAVE SEEN THIS SLIDE BEFORE IN TERMS OF THE DISPARITY OF THE DISEASE ACROSS THE WORLD, PREDOMINANTLY IN ASIA AND SUB-SAHARA AFRICA AND AGAIN RISING IN THE UNITED STATES. THERE ARE MANY DIFFERENT -- RISK FACTORS, ALCOHOLISM, METABOLIC SYNDROME, FATTY LIVER DISEASE AND THIS CONTRIBUTES TO THE HETEROGENEITY OF THE DISEASE WE SEE IN THE UNITED STATES. INCIDENT RATES ARE RISING BUT IN DIFFERENT GROUPS OF PATIENTS. IN FACT, HISPANIC AND BLACK POPULATIONS HAVE A HIGHER LITTLE OF INCIDENCE THAN DO OTHER POPULATIONS SO WHY IS THIS THE CASE? AND ACROSS ASIA, YES, THEY HAVE A HIGHER PREDOMINANCE OF THE DISEASE BUT ALSO A DIVERSE ETIOLOGY. SO IN CHINA, IT IS PREDOMINANTLY A HEPATITIS B ASSOCIATED DISEASE WHEREAS IN JAPAN, THERE IS A HIGHER LEVEL OF HEPATITIS C. IN MONGOLIA, THERE IS A UNIQUE POPULATION OF HEPATITIS C AND D VIRUS AND CONDUCTING STUDIES IN THAILAND WITH A VERY HIGH LEVEL OF HCC WITH HEPATITIS B INFECTION AND A LIVER FLUKE INFECTION FROM EATING DISHES WITH RAW FISH THAT ARE CONTAMINATED WITH THE PARASITE. SO WE HAVE BEEN STUDYING LIVE CANCER IN THE PAST DECADE, THEY HAVE A HIGH PREVALENCE OF CARCINOMA AND CALANGEO CARS MOMENT MA, ANOTHER TYPE OF LIVER CANCER AND IN THE NORTHEAST REGION, IT IS QUITE HIGH AND CORRELATES WITH THE AMOUNT OF LIVER FLUKE INFECTION OF THIS PARTICULAR PAR PARASITE. THIS SET ABOUT TO IDENTIFY A CLINICAL RERELEVANT BIOMARKER FOR RISK ASSESSMENT, EARLY DETECTION, TUMOR CLASSIFICATION AND PROGNOSIS OF PATIENTS WITH LIVER CANCER. INDIVIDUALS WITH CHRONIC LIVER DISEASE, INDIVIDUALS WITH HEPATITIS OR ALCOHOLIC LIVER DISEASE WHO ARE PRONE TO DEVELOPING LIVER CANCER, INDIVIDUALS WITH PARASITE INFECTION WHO ARE KNOWN TO DEVELOP COLANGEAL CANCER. THE RESULTS OF THE 200 OR SO PATIENTS ACROSS THIS COHORT, LOOKING AT EXPRESSION PROFILES, WHAT WE FOUND IS THERE ARE SUBGROUPS OF HCC AND OTHER CANCER THAT CAN BE DEFINED BY GENUS EXPRESSION AND WE ASK IF THEY WERE UNIQUE TO THE POPULATION OR COULD THEY BE FOUND IN OTHER POPULATIONS SO THIS STUD DEWAS DONE TO COMPARE THE COHORT WITH CHINESE PATIENTS, ASIAN AMERICAN PATIENTS IN THE UNITED STATES AS WELL AS JAPANESE PATIENTS AND WHAT WE SAW IS THESE SUBTYPES, THE POOR AND THE GOOD SURVIVAL SUBTYPES WERE FOUND IN ALL THE ASIAN GROUPS WE INTERROGATED SHOWN IN THE RED SQUARES. AND LIKE IN THE THAI COHORT, THEY SHOWED THE SEPARATION OF PATIENTS AS A SUBGROUP THAT COULD BE DEFINED BY SURVIVAL SO THE C1 GROUP IN ALL THE COHORTS HAVE THE LOWEST SURVIVAL RATE. HOWEVER AS WE LOOKED AT THE OTHER GROUPS, WHILE WE COULD SEE PARTICULAR SUBTYPES SHOWING UP, WE COULD NOT SEE THE DATA WITH PATIENT OUTCOME SO EVEN THOUGH WE CAN SEE SIMILAR GENE EXPRESSION PROFILES IN CERTAIN INDIVIDUALS, THEY DO NOT NECESSARILY EXTEND TO AN ASSOCIATION WITH PATIENT SURVIVAL. AND SO CERTAIN SUBTYPES CAN BE FOUND IN CERTAIN RACES, IN THIS CASE, ASIANS, BUT NOT IN CAUCASIANS AND THIS MIGHT BE INFORMATIVE IN THE FUTURE OF HOW WE TREAT CERTAIN INDIVIDUALS NOT ONLY BY WHAT IS GOING ON MOLECULALY BUT BY THEIR BACKGROUND EXPRESSION. THE OTHER SUBTYPES WHERE THERE IS HIGH INCIDENCE OF LIVER CANCER IS IN MONGOLIA, A HIGH HEPATITIS D INFECTION AND THAT IS UNIQUE FROM OTHER PARTS OF THE WORLD AND WE DON'T UNDERSTAND WHAT THE UNDERLYING RISK FACTORS ARE IN THIS POPULATION. SO IS IT HEPATITIS, OTHER THINGS LIKE ALCOHOL CONSUMPTION AND OBESITY? SO AFTER RECENTLY INTERROGATING SPECIMENS FROM MONGOLIA AND COMPARING THEM TO OTHER PARTS OF THE WORLD, HERE IS JUST AN EXAMPLE OF MUTATION SIGNATURES AMONG THESE POPULATIONS SO THIS IS LOOKING AT MUTATIONS IN THE TUMOR AND WHAT WE CAN SEE HERE ARE THE PATTERNS OF MUTATIONAL SIGNATURES, SOME ARE SIMILAR, SOME ARE DIFFERENT, SOME ARE QUITE UNIQUE AND THIS IS SHOWING US AGAIN THERE IS A CERTAIN ETHNICITY OF DIFFERENTIATION IN CERTAIN POPULATIONS OF LIVER CANCER PATIENTS AND SOME OF THOSE ARE ASSOCIATED WITH ENVIRONMENTAL FACTORS SUCH AS ACID IN CERTAIN HERBAL MEDICATIONS AND AFLOTOXIN WHICH IS A RESULT OF POOR FOOD STORAGE. SO NOT ONLY ARE WE STUDYING PATIENTS THROUGHOUT THE WORLD BUT WE WANT TO INVESTIGATE MORE PATIENTS IN THE U.S. SO IT PROMPTED US TO LAUNCH THE LIVER CANCER STUDY HERE AT NCI IN 2018, HOPING TO EXPAND THE RESEARCH AT NIH TO FOCUS ON EARLY AREAS SUCH AS DETECTION, DIAGNOSIS, TREATMENT AND POPULATION STUDIES TO COMPARE AND CONTRAST. THE POPULATION HERE VERSUS THOSE IN ASIA AND OTHER PARTS OF THE WORLD. SO HERE IS OUR WEBSITE FOR FURTHER INFORMATION AND SOME OF THE SPECIFIC AIMS AND OVERALL OBJECTIVES OF THE LIVER CANCER PROGRAM HIGHLIGHT SOME OF THE THINGS I HAVE DISCUSSED TODAY IN SELLERS OF OUR RESERVE DIRECTION, IDENTIFYING NOVEL DIAGNOSTICS, UNDERSTANDING ANYTHING ABOUT IMMUNOTHERAPY, AND OTHER AREAS OF RESEARCH THAT I DIDN'T HAVE TIME TO DISCUSS TODAY LIKE EARLY CHILDHOOD LIVER CANCER. SO I HAVE DISCUSSED THREE MAJOR AREAS OF RESEARCH DIRECTIONS IN THE LABORATORY. THE FIRST WAS GENOMIC IMPLICATIONS LOOKING AT HETEROGENEITY, THEN TRYING TO IDENTIFY GROUPS THAT ARE MORE HOMOGENEOUS AND I HAVE SHOWN YOU HOW WE DO THIS WITH THE BULK TUMOR OF THE LIVER. IN TERMS OF THE IMMUNE TYPE, WE CAN LOOK AT MICROINHIBITORS, LOOKING AT THE T-CELLS AND MACROPHAGES AND TRY TO UNDERSTAND WHY PATIENTS RESPOND TO IMMUNOTHERAPY FOR EXAMPLE AND OTHER MAY NOT AND THEN FINALLY I HAVE DISCUSSED A LITTLE ABOUT HEALTH DISPARITY, GENE EX GO SUPPRESSION STUDIES, MICROSTUDIES, GENDER DIFFERENCES IN HCC AS WELL AS UNDERSTANDING DIFFERENCES IN ETIOLOGY, HEPATITIS INFECTION FOR EXAMPLE AND RACE AND ETHNICITY DIFFERENCES AROUND THE WORLD. SO I WOULD LIKE TO END BY THANKING ALL OF OUR COLLABORATORS. WE HAVE MANY IN THE U.S. AND ACROSS THE WORLD AND OF COURSE ALL THE PATIENTS THAT CONTRIBUTE TO ALL OF THE STUDIES I HAVE SHOWN TODAY. SO THANK YOU. [APPLAUSE] >> WELL, I HOPE THAT WE HAVE SOME QUESTIONS ABOUT THIS REALLY FASCINATING GLIMPSE INTO HOPEFULLY YOUR FUTURE, RIGHT? >> HOPEFULLY. >> USE THE MICROPHONE, PLEASE. >> HI, YOU GAVE A REALLY GREAT TALK. SO I KNOW THAT VIRAL INTEGRATION CAN LEAD TO GENOMIC INSTABILITY AND LIKE INSERT LARGE FOREIGN PIECES OF DNA INTO THE HOST GENOME. ARE YOU CONSIDERING USING LONG RANGE SEQUENCING TECHNOLOGIES TO GET A BETTER IDEA OF LIKE CHARACTERIZING THESE POSSIBL INSERTS? >> YES, SO WE'RE DOING THAT. HEPATITIS IS WELL-KNOWN TO INTEGRATE INTO THE GENOME AND ALTER PARTICULAR GENES, P53, ET CETERA. SO WE HAVE LOOKED INTO THAT A BIT IN THE PAST AND DOING IT NOW IN A MORE DEFINED LEVEL NOW WITH SEQUENCING STUDIES SO WE'RE USING THE LONG-RANGE. >> AND THE AUTO SEQUENCING LIKE PAC VIRAL AND -- >> YES. >> AND THE SECOND QUESTION RELATED TO T-CELLS, WHAT IS THE FUNCTION OF THAT SPECIFIC SUBSET OF T-CELLS BECAUSE I SAW THE BREAKDOWN OF IMMUNE CELLS. DID YOU LOOK AT THOSE SPECIFICALLY BECAUSE I KNOW THERE IS A HIGHWAY POPULATION OF THOSE IN THE LIVER AND WONDERING WHAT IS THE ROLE OF THOSE IN THE POPULATION YOU LOOKED AT. >> HAVE I LOOKED SPECIALLY AT THEM, OKAY, WHAT I HAVE SHOWN TODAY IS MORE OF A BROAD OVERSUE OF WHAT WE -- OVERVIEW OF WHAT WE KNOW ABOUT THE IMMUNE CELLS AND LEVELS AND WHAT ACTIVATION MAY BE BUT WE HAVE MANY STUDIES IN THE LABORATORY LOOKING AT SPECIFIC POPULATIONS OF CELLS AND HOW MECHANISTICALLY MAY BE DOING DIFFERENT FUNCTIONS IN THE LIVER. >> YOUR TALK WAS A LITTLE HARD TO FOLLOW WHEN SHOWING US THE PRINCIPLES OF THE METASTATIC AND NONMETASTATIC DISEASE BUT I COULDN'T FOLLOW WHAT WAS PREDICTIVE OF -- >> SO I SHOWED YOU TWO STUDIES, ONE CAME FROM THE TUMOR, THE OTHER FROM THE NONTUMOR. SO FROM THE TUMOR, WE HAVE A LARGE SET OF GENES THAT WERE PREDICTIVE OF METASTATIC DISEASE, THE OTHER OF PATIENT OUTCOME AND WE HAVE DONE FURTHER STUDIES TO SHOW MECHANISTICLY, ASSOCIATED WITH HCC METASTASES IN OUR STUDY. >> BUT HOW ABOUT PROTEO MIX BECAUSE THAT SEEMS SO PROMISING -- >> IN OUR LABORATORY, WE DON'T HAVE THAT MIX, WE HAVE A STUDY GOING ON BUT IT IS DIFFICULT TO STUDY BECAUSE OF ALTERATIONS OF THE PROTEIN, THAT BE WITH ALTERED IN CERTAIN WAYS, ADDED SO TRYING TO UNDERSTAND HOW WE MEASURE THE PROTEIN LEVEL PROPERLY AND THEN HOW DO WE ANALYZE THE DATA. >> SO DO YOU HAVE A THEORY IN TERMS OF THE SEX DIFFERENCE, DOES IT HAVE TO DO WITH HORMONES OR WHAT? >> WE DON'T REALLY KNOW. THAT IS A GOOD QUESTION. WE HAVE DONE A FEW TESTS ON ESTROGEN RECEPTOR LEVELS AND PERHAPS MECHANISMS THAT COULD INDICATE WHY TEAMS HAVE A LOWER LEVEL OF HCC INCIDENCE BUT I HAVE TO SAY THERE HAS NOT BEEN A LOT OF STUDIES TOWARDS THE GENDER DISCREPANCY AS OF YET BUT THERE ARE LABS WORKING SPECIFICALLY ON THIS QUESTION. [ OFF MIC ] >> THAT, I DON'T THINK I -- >> CAN YOU REPEAT THE QUESTION? >> IN TERMS OF DIFFERENCES OF INFECTION BETWEEN MALES AND FEMALES, I DON'T THINK WE HAVE AN ANSWER TO THAT. >> WELL, IF THERE ARE IN FURTHER QUESTIONS, I WANT TO THANK YOU BOTH VERY MUCH FOR REALLY A VERY EXCITING PRESENTATIONS AND POINTING OUT NOT ONLY THE COMPLEXITY OF THIS INCREASING PROBLEM BUT ALL THE MANY APPROACHES THAT ARE BEING TAKEN IN AN ATTEMPT TO UNDERSTAND WHAT IS GOING ON -- [ OFF MIC ] [APPLAUSE]