Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov TODAY'S LECTURE IS PART OF OUR CLINICAL GRAND ROUNDINGS GREAT TEACHER SERIES TODAY WE HONOR THE LEGACY OF DR. JOHN DECKER, WHO SERVED FROM 1983-1990. DURING HADIS TENURE AS DIRECTOR ADVANCES AT THE CLINICAL CENTER INCLUDED DEVELOPMENT OF THE POSITRON EMISSION TOMOGRAPHY PROGRAM, INITIATION OF THE USE OF MAGNETIC IMAGES AND MARSHALING OF SUPPORT AGE RESEARCH. I'M ESPEBLLY HONORED AND PLEASED TO WELCOME THE DECKER FAMILY WHO ARE JOINING US TODAY VIRTUALLY. NOW, I WOULD LIKE TO TURN THE PODIUM OVER TO MISS SANDRA HOYE ADVANCE ASSOCIATE FOR THE FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH FOR REMARCOS BEHALF OF THE FNIH. >> THANK YOU DR. BURKLOW. GOOD AFTERNOON AND WELCOME, MY NAME IS KACCT SANDRA HOCE AND I'M AN ADVANCE ASSOCIATE FOR THE FOUNDATION FOR THE NIH. I AM DELIGHTED TO WELCOME YOU TO THE 18th ANNUAL JOHN LAWS DECKER MEMORIAL LECTURE FEATURING THE 2022 DISTINGUISHED CLINICAL TEACHER AWARD RECIPIENT DR. JONATHAN M. HERNçNDEZ. DR. HERNçNDEZ WE LOOK FORWARD TO YOUR PRESENTATION. THE FNIH IS PROUD TO HAVE BEEN A PARTNER OF THE IMPORTANT LECTURE SINCE 2003 WHEN THE NIH BEGAN RECOGNIZING THE LATE NIH CLINICAL DIRECTOR ANNUALLY THROUGH THE CLINICAL CENTER GRAND ROUNDS LECTURE SERIES. AT THIS TIME, FRIENDS AND FAMILY OF DR. DECKER WORKED WITH THE FNIH TO ESTABLISH THE MEMORIAL FUND IN HONOR OF THEIR LATE FATHER. DURING HIS LIFETIME DR. DECKER WAS AN OUTSTANDING TEACHER WHO THRIVED TO CONNECT TO SCIENTIFIC COMMUNICATIONS AROUND THE WORLD TO ACCELERATE IMPORTANT RESEARCH. THIS IS THEIR AND OUR WAY OF EXTENDING HIS LEGACY. I WANT TO THANK THE DECKER FAMILY FOR THEIR GENEROSITY AND INSPIRED VISION IN ESTABLISHING THE DECKER MEMORIAL FUND. THE FNIH IS PROUD OF OUR LONG LASTING COLLABORATION WITH YOU AND THE CLINICAL CENTER TO RECOGNIZE INNOVATIVE ACCOMPLISHMENTS IN CLINICAL RESEARCH AND THEIR LASTING IMPACT ON TRAINING THE NEXT GROUP OF GREAT SCIENTISTS. WE INVITE TO YOU EXPLORE THE MANY PARTNERSHIPS FORMED AND THE INNOVATIVE SCIENTIFIC THINKING THAT IS SUPPORTED THROUGH OUR PROGRAMS ON THE FNIH WEBSITE, FNIH.ORG. I WILL NOW TURN THINGS BACK TO DR. BURKLOW TO INTRODUCE THE NIH CLINICAL FELLOWS COMMITTEE. THANK YOU FOR JOINING US FOR THIS EVENT AND PLEASE ENJOY THE 18th ANNUAL JOHN LAWS DECKER MEMORIAL LECTURE. >> THANK YOU MISS HOYE FOR YOUR KIND REMARKS AND ESPECIALLY TO THE DECKER FAMILY FOR YOUR CONTINUED GENERATEDDOUS SUPPORT, IT IS MUCH APPRECIATED. EACH YEAR, NIH CLINICAL FELLOWS SEEK OUT A HIGHLY REGARDED TEACHER TO RECEIVE THE CLINICAL TEACHER AWARD. DR. DECKER WAS AN INSPIRING LEADER AND MENTOR SO IT'S VERY IMPORTANT THAT THE DISTINGUISHED CLINICAL TEACHER AWARDEE DELIVERED ANNUAL DECKER MEMORIAL LECTURE. BEFORE INTRODUCING TODAY'S SPEAKER AND THE 2022 DISTINGUISHED CLINICAL TEACHER AWORRIEDEE, I WOULD LIKE TO TURN THE VIRTUAL PLATFORM OVER TO DR. MARJA BROLINSON WHO CO CHAIRS THE COMMITTEE TO,A NOUNS THE WINNER OF THE 2023 CLINICAL TEACHER AWARD. >> MY NAME IS MARJA BROLINSON AND I AM THE CLINICAL FELLOWS COMMITTEE CO CHAIR, I WOULD LIKE TO THANK DR. BURKLOW FOR HIS ONGOING SUPPORT AND THE NIH CLINICAL FELLOWS AND FOR A STRONG COMMITMENT TO THE IMPORTANCE OF MENTORING AT NIH. I AM HOONORRED TO,A NOUNS THE WINNER FOR THE 2023 DISTINGUISHED CLINICAL TEACHER AWARD. A MENTOR GUIDES PROFESSIONAL GROWTH BY HELPING TRAINEES IDENTIFY AND DEVELOP SKILLS AND TALENT, SET AND ACHIEVE GOALS, ANTICIPATE ROAD BLOCKS AND OVERCOME OBSTACLES. A CLINICAL MENTOR ALSO 'EM BODIES THE CHARACTERISTICS OF AN ETHICAL AND PASSIONAL PHYSICIAN. ALL OF THE INDIVIDUALS NOMINATED FOR THIS YEAR'S AWARD AND RECOGNITION AS OUTSTANDING CLINICAL MENTORS. I WOULD LIKE TO THANK ALL OF THE NOMINEES FOR THEIR COMMITMENT TO TRAINING CLINICAL INVESTIGATORS AT THE NIH AND THEIR OVERALL CONTRIBUTION TO MEDICAL EDUCATION. EACH YEAR, THE DISTINGUISHED CLINICAL TEACHER AWARD IS DECIDED BY A VOTE OF THE CLINICAL FELLOWS AND PRESENTED TO AN INDIVIDUAL WHO EXEMPLIFIES THE IDEA OF A MENTOR TEACHER AND CLINICIAN AND RESEARCHER. HERE ARE A FEW WORDS EXPRESSED ABOUT THIS YEAR'S AWARDEE. WITH THE UTMOST PATIENCE AND SINCERITY HE ALWAYS GOES ABOVE AND BEYOND TO TEACH THE FELLOWS HOWEVER MANY TIME ITS TAKES TO SOLIDIFY OUR KNOWLEDGE MAKING DIFFICULT CONCEPTS EASIER AND FORMING US INTO BETTER CLINICIANS. YOU CAN ALWAYS FIND HIM WITH A CUP OF COFFEE IN HAND, A JOKE IN HIS BACK POCKET AND A SMILE TWINKLING THROUGH HIS EYES BEHIND HIS MASK AS HE JUMPS BETWEEN FELLOWS TO HELP THEM GET THROUGH DIFFICULT PATIENTS. IF YOU LOOK CLOSE ENOUGH, YOU CAN FIND EXTREMELY HELPFUL CLINICAL PEARLS IN HIS MANY PUBLICATIONS. ONE PUBLISHED EXAMPLE IS HYPOCYSTITESIS AN UPPERDATEOT DISORDERS DIAGNOSE AND MANAGEMENT OF PITUITARYY INFLAMMATION, PLEASE JOIN ME IN WELCOMING OUR CLINICAL AWARD WINNER DR. SRIRAM, GUBBI, IN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES. I WOULD NOW LIKE TO TURN THE MIC OVER TO DR. BURKLOW TO INTRODUCE TODAY'S SPEAKER AND OUR 2022 DCTA AWARD WINNER. THANK YOU. >> THANK YOU DR. BROLINSON AND MANY CONGRATULATIONS TO DR. GUBBI. I'M NOW HONORED TO INTRODUCE TODAY'S SPEAKER THE A RESENT OF THE 2022 DISTINGUISHED TEACHER AWARD, DR. JONATHAN M. HERNçNDEZ. HE IS THE CHIEF OF THE SURGAL ONCOLOGY SECTION, HEAD OF THE METASTASIS BIOLOGY SECTION AT THE CENTER FOR CANCER RESEARCH AND THE NATIONAL CANCER EN--STRATEGIESITUTE AND ASSOCIATE PROFESSOR OF SURGERY FOR UNIFORM SERVICES, UNIVERSITY OF HEALTH SCIENCES. DR. HERNçNDEZ EARNED HIS MEDICAL DEGREE FROM THE UNIVERSITY OF FLORIDA IN 2005 AND COMPLETEDT GENERAL SURGERY UNIVERSITY OF SOUTH FLORIDA. DURING HIS HESIDENCY DR. HERNçNDEZ SPENT 2 YEARS AT THE MOFET CANCER RESEARCH CENTER AND INSTITUTE, FOR LIVER, METASTASIS, AND METASTATIC SPREAD TO SUPPORT THE NIH FUNDING. FOLLOWING HIS RESIDENCY HE COMPLETED SURGERY AND PSYCHOLOGY AT THE MEMORY RESPONSOR SLOAN KETTERRING CANCER CENTER. DURING FELLOWSHIP TRAINING DR. HERNçNDEZ SPENT AN ADDITIONAL 2 YEARS IN DEDICATED BASIC RESEARCH STUDYING METASTATIC COLONIZATION WHILE A SCHOLAR IN THE CELL BIOLOGY PROGRAM OF THE SLOAN KETTERRING INSTITUTE AND A VISITING INVESTIGATOR AT THE WILD MEDICAL COLLEGE OF CORNELL UNIVERSITY. DR. HERNçNDEZ JOINED THE SURGICAL ONCOLOGY PROGRAM IN 2016 AS A TENURED TRACK INVESTIGATOR. CLINICALLY HE SPECIALIZED IN THE TREATMENT OF METASTATIC AND TUMOR AND BILE DUCTS AND PANCREAS AND SURGICAL MANAGEMENT OF COMPLEX ABDOMINAL TUMORS, DR. HERNçNDEZ FOCUSED ON THE IMELEMENTATION OF AN EXVIEF O TUMOR SYSTEMS THAT ALLOW HIS LABORATORY TO FULLY CHARACTERIZE THESE IN THE OPERATING ROOM AND EVALUATE THERAPIES, AND THEY ALLOW THESE TO BUILD COMBINATION THERAPIES FOR TUMORS AND DELINEATE AND TARGET UNCHARACTERRIZED SINGLE AXIS FOR GAIN IN PATIENTS WITH COLANGIAL CARCINOMA AND ELUCIDATE MECHANISMS FOR WHICH TUMOR CELLS MARK THE ENVIRONMENT OF THIS ORGAN TO FORM LIFE THREATENING METASTASIS. DR.ENER NANOG IT DES IS BOARD CERT TIE INDEED GENERAL SURGERY AND COMPLEX GENERAL SURGICAL ONCOLOGY BY THE AMERICAN BOARD OF DIRECTORS OF SURGERY. MEMBER OF THE AMERICAN ASSOCIATION FOR CANCER WERE, ASSOCIATE FOR SURGICAL ONCOLOGY, AMERICA'S PAN KRE TINSAT OLDER PEOPLE ASSOCIATION, SOCIETY OF UNIVERSITY SURGEONS AND AMERICAN COLLEGE OF OF SURGEONS, DR. HERNçNDEZ HAS AUTHORED OVER 100 PEER PUBLICATIONS AND NUMEROUS BOOK CHAPTERS AND AUTHORITATIVE TEXTBOOKS. HIS TALK TODAY IS ENTITLED THE DEVELOPMENT AND IMPLEMENTATION OF EXVIVO HUMAN TUMOR SYSTEMS FOR TRANSLATIONAL SCIENCE. PLEASE WELCOME OUR SPEAKER DR. JONATHAN HERNçNDEZ. THANK YOU SO MUCH, TOM THANK YOU FOR THE INTRODUCTION, MARJA, THANK YOU ABOUT THE KIND WORDS ABOUT MENTORING AND TEACHING AND THE TIELT OF MY TALK IS AGAIN IS THE DEVELOPMENT AND IMPLEMENTATION OF EXVIVO HUMAN TUMOR SYSTEMS FOR TRANSLATIONAL SCIENCE. I WANT TO START WITH A FEW COMMENTS, THIS IS A HUMBLING AWARD TO BE HONOR WIDE, I DON'T NECESSARILY SEE MYSELF AS A MENTORSHIP SKILL OR OR A TEACHER, INSTEADY I SORT OF THINK ABOUT THE PEOPLE WHO WORK WITH ME AND WORKED WITH ME THROUGH THE YEARS AS SORT OF PARTNERS AND THIS HAS BEEN A MUTUALLY BENEFICIAL RELATIONSHIP AND SO I--INSTEAD OF SORT OF TALKING ABOUT A GIVEN TOPIC, WHAT I WANT TO DO IS HIGHLIGHT THE ACHIEVEMENTS OF MY PARTNERS, MY CLINICAL FELLOW PARTNERS OVER THE LAST SEVERAL YEARS, SO THAT'S WHAT I WANT TO SPEND THE NEXT 40 MINUTES AND SO I WILL DO THAT IN THE CONTEXT OF SORT OF 3 AREAS, BUT FIRST I WILL TALK ABOUT EXVIVO LIVER SYSTEM AND SECONDLY I WILL TALK ABOUT THE SMART SYSTEM AND TELL WHAT YOU THAT IS AND LAST I WILL TALK ABOUT USING THE TOOLS SO THOSE WILL BE 2 SEPARATE ROUTES THAT I SHOW HOW WE UTILIZE THESE TUMOR SYSTEMS AND THAT'S HOW WE WILL DO THIS. SO I THINK ABOUT HUMAN TUMOR SETS SORT OF VERY COOL, VERY UNIQUE THINGS THAT HAPPEN UNFORTUNATELY TO PEOPLE. IT'S VERY HARD TO REPLICATE AND YOU THINK ABOUT IT WHERE WOULD YOU EVEN GO TO GET TUMORS, YOU VALID TO GO TO PATIENT WHO IS DEVELOP THESE, THEY'RE VERY COMPLICATED AND I HAD THIS IDEA THAT ALL THESE PRECLINICAL MODELS ARE AVAILABLE TO US, THEY DON'T--THEY DON'T REPLICATE WHAT WE ACTUALLY SEE AND FEEL IN PEOPLE WHEN WE OPERATE ON THEM EVERY DAY. DISP SO I HAD THIS IDEA THAT WE SHOULD INSTEAD MAYBE UTILIZE THE TUMORS THAT WE'RE TAKING OUT OF PEOPLE IN A DIFFERENT WAY, DON'T PUT THEM IN A FREEZER, DON'T JUST SEQUENCE THEM, BUT ACTUALLY USE THEM SO I HAD THIS IDEA THAT WE WOULD DO THE FOLLOWING, SO I'M A LIVER SURGEON, I SPEND A FAIR AMOUNT OF TIME DOING LIVER SURGERY, INSTEAD OF TAKING OFF A THIRD OR A QUARTER OF SOMEBODY'S LIVER SO I CAN TAKE OFF THE TUMOR, I WOULD INSTEADY TAKE THIS DOWN THE HALLWAY TO A PROFUSION MACHINE AND KAN--KANAUE LATE IT AND KEEP THE THING VIABLE AND IF I COULD DO THAT, THAT WOULD THEN BE AS REAL AS THINGS WOULD EVER BE AND WHATEVER QUESTIONS WE ASKED WOULD BE TRANSLATIONALLY RELEVANT AND THEN WE COULD START DOING REALLY COOL EXPERIMENTS LIKE THE FOLLOWING, WE COULD GIVE VARIOUS DRUGS DEPENDING ON WHAT WE ALREADY KNEW ABOUT THE TUMOR BEFORE WE OPERATED ON THE PASHT AND THAT COULD BE BASED ON MUTATIONAL STATUS OR SOME SORT OF TRANSCRIPT THAT THE TUMOR WAS EXPRESSING, OF COURSE, NOW, A LOT OF THINGS ARE FOCUSED ON IMMUNOTHERAPY AND ACTIVATING THE IMMUNE SYSTEM IN THE TUMOR, AND IT'S CERTAINLY FOCUSED DRUGS ON THESE EFFORTS. THESE ARE VERY HARD TO RECAPITULATE OUTSIDE OF PATIENTS, AND IT WILL GIVE CELL THERAPY INTO OUR SYSTEM AND NONE OF THIS WOULD HARM ANY CAUSE OF HARM TO THE PATIENT BECAUSE EVERYTHING WOULD BE OUTSIDE THE PATIENT AND SO THIS WAS A CONCEPT I SORT OF CAME WITH. SO I--YOU KNOW I GOT HERE IN FALL OF 2016 AND I AGREED TO TAKE SEVERAL FELLOWS IN THE LAB, JULY OF 2017, I TOOK 3 AGAINST THE ADVICE OF MANY PEOPLE. I COULDN'T TALK THEM OUT OF IT, THEY SIMPLY WOULDN'T LISTEN AND SO WE STARTED A PARTNERSHIP AND WE SAID OKAY, LET'S SEE IF WE CAN MAKE THIS COME TO FRUITIONS AND WE CONVINCED THE POWERS THAT BE AT NCI THAT WE NEED A TRANSPLANT TRANSFUSION MACHINE, AT THE TIME NONE OF THIS WAS APPROVED IN THE FDA, WE BOUGHT IT WITH FROM A COMPANY IN EUROPE, WE DEVELOPED A BACK TABLE SET UP AND PLANNED EVERYTHING, WITH THE APPROVAL OF THE NCI AND PLANNED IT APPROPRIATELY AND SAM AND 2 OF THE FELLOWS THAT REALLY WORKED DAY AND NIGHT ON THIS ARE SAM ROUGH AND MIKE [INDISCERNIBLE]. THEY WOULD SORT OF WALK THE LIVER DOWN THE HALL AND REALLY SPEND THE NIGHT NEXT TO THE MACHINE, THEY HAD A BET IN THE LAB AND THEY WOULD SPEPPED THE NIGHT NEXT TO THE MACHINE AND WE DID THIS SEVERAL TIMES SO THIS WAS THE FIRST PATIENT WE DID. YOU CAN SEE A LESION THERE, THIS IS A CO LANCHIAL CARCINOMA. WE CANNULATED THE VASCULARRURE AND PUT IT ON THE MACHINE AND FOR OUR FIRST HUMAN RUN DIDN'T GO POORLY BUT CERTAINLY NOT WHAT WE INTENDED, THIS ONLY LASTED 11 HOURS, OUR GOAL WAS ABOUT A WEEK SO WE COULD PERFORM ALL SORTS OF REALLY COOL EXPERIMENTS, WE DID THIS AGAIN ON A PATIENT, THIS WAS A COLORECTAL LIVER METASTASIS, WE GOT BETTER AT IT AND AT THE TIME WE WERE ABLE TO KEEP THIS THING VIABLE AND DIDN'T REALLY GET BETTER BUT WE WERE A BIT SLICKENER DOING THIS, I THINK AN IMPORTANT POINT I LEARNED EARLY WAS WAS THAT EVEN THOUGH THE LIVER WAS NOT HAPPY ON OUR MACHINE EARLY ON, THE TUMOR REMAINED VERY HAPPY AND THAT'S SORT OF THE PROBLEM, RIGHT? TUMORS DON'T DIE. AND SO THIS WAS AT LEAST CONCEPTUALLY, WE WERE ENTHUSIASTIC BY THE CONCEPT THAT THE TUMOR REALLY REMAINED OKAY. NOW, SAM AND MIKE CONVINCED ME WE SHOULD GO TO GONIGAN, IN THE NETHERLANDS WHERE THE PEOPLE MADE THIS MACHINE BECAUSE THEY ALLOWED US TO GET PIG LIVERS OVER AND OVER AND OVER THERE WITHOUT HAVING TO BURN THROUGH OUR LABORATORY BUDGET ON DISPOSABLES, SO I TELL THEM WE TOOK A VACATION TO THE NETHERLANDS, BUT THE TRUTH IS IT WAS NOT A VACATION BUT THEY TOOK TURNS SPENDING THE NIGHT IN THE WAREHOUSE PROFUSING LIVERS, NOW WE GOT BETTER AT IT BUT WE GET BETTER, I WILL SHOW YOU DATA FROM THE THIRD PERSON WE DSO THIS TUMOR WAS ANOTHER COLORECTAL LIVER METASTASIS, WE CANNULATED EVERYTHING, WE GOT BETTER AT THIS, YOU CAN SEE THE ARTERIAL AND VENOUS LINES, THE VENUS LINE WAS EXTRACTING OX GENERATED. IT MADE BILE, THE BILLIARY COMPOSITION LOOKED REASONABLE, BUT WHAT YOU CAN SEE AT ABOUT 24 HOURS IS THE LEVELS BEGIN TO CLIMB AND BY 48 HOURS BY ABOUT 2 DAYS THE LIVER LOOKED BASICALLY NONVIABLE. THE TUMOR HOWEVER, AGAIN AT THE END OF THE RUN, AGAIN THE PROBLEM WITH TUMORS THEY DON'T DIE, THE TUMOR STAYED QUITE VIABLE AND QUITE HAPPY AND I EVEN CONVINCED THEM FROM DR. ROSENBERG'S LAB TO COME DOWN, TAKE A PIECE OF THE LIVER AND DO THEIR TILL HARVEST FROM THIS AND THAT SEEMED TO WORK VERY WELL IN MY MIND SO THE TOMB ARE WAS HAPPY, THE TUMOR IMMUNE MICROENVIRONMENT WAS HAPPY, WE JUST WEREN'T VERY GOOD YET AT PROFUSING ORGANS. SORT OF WHAT WAS DEJECTED A LITTLE BIT AND THE TEAM SORT OF--WE HAD TO RECENTER OUR THINKING AND SO AS TIME WENT BY, I HAD NEW FELLOWS JOIN THE LAB, NOW PARTNERS IN ALL OF THIS AND WE HAD A NEW IDEA NAWE NEEDED TO COMPLETELY GET RID OF THE OLD MACHINE AND THIS WAS LED BY ALEX AND A POST BACKTHAT HE WANTED IN THE LAB VERY MUCH, ALAN LUNA AND WE NAMED THE SYSTEM AFTER ALAN AND SO A LOT OF PEOPLE HAVE CONTRIBUTED TO THIS, JACOB LANDEN CARRY RYAN, STEPHANIE AND LAILA, AND A LOT OF PEOPLE CONTRIBUTE TO THIS, BUT WE REDESIGNED THE SYSTEM IN ENTIRETYY AND SO WE'VE BASICALLY DECIDE THAD WE WOULD HAVE TO BUILD EACH OF THE ORGAN SYSTEMS AROUND THE LIVER IN ORDER TO KEEP THIS THING VIABLE AND HAPPY FOR A PROLONGED PERIOD OF TIME AND THAT INVOLVED THE ADRENAL GLAND, PANCREAS, HEART AND LUNGS, WE HAD THAT BEFORE BUT WE NEED TODAY TO OPTIMIZE THAT, WE HAD TO ADD IN A DIALYSIS CIRCUIT, WE WOULD ADD IN THE GUT SO WE WOULD ADD IN BIOSALT AND NUTRIENTS TO SORT OF GIVE YOU A TASTE OF WHAT THIS LOOKS LIKE YOU KNOW WE DESIGNED A SEMIAUTOMATED SYSTEM FROM THE DAYS WHEN SAM AND MIKE WERE SLEEPING NEXT TO THIS THING, MASSAGING THE LIVER EVERY COUPLE OF HOURS TO SORT OF TRY AND GET RID OF THE EDEMA, OLYMPIC EXPECTATIONS AND THE TEAM DECIDED THAT WE SHOULD HAVE A CENTRAL NERVOUS SYSTEM SUCH THAT ANY PARAMETERS THAT WERE BREECHED, WE WOULD AUTOMATICALLY INFUSE VARIOUS BASAL ACTIVE SUBSTANCES, NOW THIS DIDN'T OBVIATE THE NEED TO SLEEP NEXT TO THIS, I DON'T WANT TO DOWN GRADE THIS SORT OF LEVEL OF COMMITMENT THAT THE FELLOWS HAVE HAD OVER THE TIME, BUT WE DEVELOPED A CENTRAL NERVOUS SYSTEM TO SEMIAUTOMATE THINGS. WE HAD ISSUES WITH HOMOLYSIS AND SO, THE TEAM HACKED INTO A ROTOFLOW PUMP SUCH THAT WE COULD CONTROL THIS PUMP SEMIAUTOMATICALLY AND THIS WAS ASSOCIATED WITH FAR LESS HOMOLYSIS, THE DIALYSIS WAS A PROBLEM FOR US BECAUSE WE HAD TO CONTROL THE DISCIPLINARIAL SAIT VOLUMES AND CONTROL THINGS SO THE TEAM CIRCUMVENTED THESE PROBLEMS BY USING 2 SEPARATE PROMPTS 1 BEFORE AND AFTER THE DIALYSIS FILTER AND WE COULD CONTROL THE SPEED AND DETERMINE IF WE WANT TO PUT FLUID INTO THE DIALYSIS OF THE SYSTEM OR TAKE OFF AND YOU CAN SEE THAT THE URINE LOOKS LIKE URAIN BASICALLY SO WE EALZ REALIZED THAT OVERTIME AS I'M SIGHTING HERE TALKING TO YOU AND BREEGING MY DIAPHRAGM IS MOVING UP AND DOWN AND I'M COMPRESSING MY LIVER AND SO WE FELT LIKE THAT WOULD BE AN IMPORTANT COMPONENT OF THIS AS WELL, SO, WE DESIGNED AND IMPLEMENTED A DIAPHRAGM IF YOU WILL AND THIS WAS CONTROLLED BY A PORTABLE VENTILATURE SUCH THAT THE GRIEVING DYNAMICS WERE SIMILAR TO THAT OF A PERSON AND FINALLY, YOU KNOW THE TEAM DEVELOPED THIS GLUCOSE SENSOR WHICH WOULD BE THE SAME SENSOR A DIABETIC PATIENT WOULD HAVE EMBEDDED IN THEIR SKIN, WE HAD TO ENGINEER AN ADAPTER SUCH THAT WE COULD GET CONSTANT GLUCOSE FEEDBACKS SO WE WOULD KNOW WHETHER THE SYSTEM NEEDED INSULIN OR GLUE CODON, I WANT TO HIGHLIGHT THE COMPLEXITY BEFORE I SHOW IT TO BECAUSE IT'S TOO COMPLICATED TO GO THROUGH IT IN THE PICTURE BUT SUFFICE IT TO SAY THAT THIS IS YEARS OF WORK AND THIS IS A WORKABLE SYSTEM UNLIKE THE 1 WE PURCHASED. THIS WAS OF OUR OWN DESIGN AND OF OUR OWN MAKING AND I REALLY WANT TO CREDIT THE FELLOWS INVOLVED OVER THE PERIODS OF TIME WHO REALLY MADE THIS HAPPEN AND THEY MADE THIS COME TO FRUITION AND THEY DID THIS BY MANY, MANY SLEEPLESS NIGHTS. AND SO, I WANT TO GO THROUGH HOW WE OPTIMIZE IT SO WE DESIGNED IT AND THEN, OF COURSE, HOW ARE WE GOING TO OPTIMIZE THIS SO WE DECIDED THAT WE WOULD--SOME OF THE FELLOWS IN THE LAB FOUND A SLAUGHTER HOUSE AND SO, I HAVE NOT BEEN. THEY DON'T INVITE ME BUT THEY GO TO A SLAUGHTER HOUSE AND THEY GO UP THERE AS BEST I CAN TELL THEY HAVE A GREAT TIME AND THEY GO TO MOWPT AIRY AND GET PIGGINGS FROM THE LIVERS FROM THE SLAUGHTER HOUSE, THEY GET BLOOD AND SOMETIMES THEY WILL BRING BACK TREATS, THEY DON'T SHARE WITH ME NECESSARILY, BUT, AND SO THEY BRING BACK TREATS AND THEY COME BACK TO THE NIH WITH THE ORGANS AND WE OPTIMIZE THAT WAY. I'M NOT GOING TO SHOW YOU ANY DATA ABOUT PIG LIVERS BUT THIS IS A PATIENTS IN THE CLINIC UPPER OF ME ASSISTING DR. LAMBEDDEN, HE WAS TAKING OUT THIS LIVER AND THIS IS STEPHAN EXPE JACOB AND THEY'RE CANNULATING ON THE BACK TABLE AND LONG AND SHORT IS, ALL OF THE HARD WORK PAID OFF. THIS IS A VERY RECENT PICTURE OF US AND WITH A PATIENT WHO THIS IS THE PATIENT, HER LIVER'S BACK BEHIND HER, THIS IS POST OPERATIVE DAY NUMBER--6 DAYS AFTER WE PUT HER LIVER ON THE SYSTEM. THIS IS ALAN, STEPHANIE 2 VERY BRIGHT POST BACKSTUDENTS AND JACOB, YOU SAY JACOB TAKING OUT THE PATIENT'S LIVER WITH ME,A CYSTING AND HERE'S THE PATIENT SO ALL OF OUR STRUGGLES AND ALL OF OUR EFFORTS STARTED BY SAM AND MIKE AND REALLY SORT OF CAME TO FRUITION BY A TEAM LED BY ALEX, JACOB AND OTHERS, REALLY IT WORKED AND THE LIVER LOOKED GOOD AND IMPORTANTLY THE TUMOR LOOKED GOOD AND THIS IS A NEUROENDOCRINE TUMOR AND I THINK THIS IS IMPORTANT BECAUSE AS YOU THINK ABOUT NEUROENDOCRINE TUMORS THEY ARE NOT GOOD IF ANY PRECLINICAL MODEL OF VALUE SO HAVING A SYSTEM LIKE THIS FOR VAR TUMORS WHERE YOU DON'T HAVE A MOUSE MODEL, YOU DON'T HAVE, YOU KNOW PATIENT DERIVED EXTEN O GRAPHS TO UTILIZE, THESE ARE TRUE OF NEUROENDOCRINE TUMORS, THIS BECOMES A REALLY VALUABLE TOOL AND BASED WHERE THERE AREN'T ANY OTHER OPTIONS. SO AGAIN, THE TEAM WE MIGHT HAVE HAD A BOTTLE OR 2 OF CHAMPAGNE TO CELEBRATE THIS 1 AND I WOULD SAY THAT I AM VERY HAPPY WITH THE WAY THE TEAM CAME TOGETHER AND REALLY OVERCAME A LOT OF OBSTACLES. OKAY, I DIDN'T REALLY EXPANDOT AMOUNT OF FRUSTRATIONS WE SAW IN THAT SYSTEM TO MAKE IT WORK. IN THE MIDDLE OF THAT I DECIDED WE SHOULD PIVOT AND WE HAD AN IDEA THAT MAYBE, YOU KNOW IF YOU THINK OF THE LIVER AS THE CADILLAC, IT'S THE TRUEST PRECLINICAL MODEL YOU COULD EVER HAVE, IT HAS THE CIRCULATORY SYSTEM, HAS ALL THE COMPONENTS BUT WHAT IF WE COULD DO THIS ON A SMALLER SCALE. AND SO THIS ALSO WAS A VERY LONG TIME IN THE MAKING AND ULTIMATELY CULMINATED IN THIS SORT OF IDEAL WAS SOMETHING THE FELLAS MADE SYSTEM CALLED SMART SYSTEM, THIS STANDS FOR SURGICALLY RESECTED MESOTHELIUM CONTAINING UNAFFAIRS TEAM LEADERRERRED TUMOR MICROENVIRONMENT. I WON'T SHOW YOU WHAT IT LOOKED LIKE EARLY ON BECAUSE IT'S LAUGHABLE TO BE HONEST BUT UNDER ALEX, JAMES AND STRAYA, GUPTA AND EMILY WITH THE HAD BEEN OF NEWER MEMBERS, CARRY AND RON AND STEPHANIE, THEY BROUGHT THIS TO FRUITION, AND SO WHAT THIS IS IS THIS LOOKS LIKE WHEN A PATIENT HAS METASTASIS ON THE LINING OF THEIR ABDOMINAL CAVITY THIS, IS POETIC THE PERO TONEM, DIAGNOSTICALLY OR THERAPEUTICALLY IT'S INDICATED WE WOULD REMOVE THIS LINING AND WE WOULD THEN PUT THIS ON TO PLATFORMS ALMOST LIKE A MODIFIED CHAMBER, WE DRAW THE PATIENT'S BLOOD BEFORE HAND AND WE COLLECT THEIR PLASMA, SUCH THAT THESE PROFUSION CHAMBERS ARE BATHED INOX GENERATED 8ED PLASMA FROM THE SAME PATIENT AND WE USED POINT OF CARE INSTRUMENTS TO MAKE SURE NORMAL PHYSIOLOGY IS MAINTAINED AS BEST WE CAN. AND THEN WE CAN CERTAINLY CONCEIVE OF ADDING DRUGS INTO THIS CIRCUIT SUCH THAT IT WOULD MIMIC THE PATIENT'S PLASMA LEVELS OF THE DRUG AND THEN WE CONCEIVED AFRONS AN IMPLEMENT THE MULTIPLE IMAGING, MULTIPLE INTERROGATION PILLARS, PILLARS OF INTERROGATION, SOME OF THESE ARE ADVANCED IMAGING, FLOW CYTOMETRY, ALL OF THE OMICs YOU CAN THINK OF AND THEN WE LOOK AT THE PROFUSATE IN THE PLATMA AS A WAY TO IDENTIFY BIOMARKERS OF RESPONSE OR NOT. SO THIS WAS A WAY--THIS IS TD WAY WE DO THIS. SO WE PUT A SCOPE IN SOMEBODY'S ABDOMEN AND WE'RE LOOKING FOR THESE METASTASIS AND HERE CAN YOU SEE WE'RE REMOVING THIS VERY THIN LAYER BLUNTLY AND DOING THIS VERY GENERALLY, ALTHOUGH I GUESS IT MAY NOT LOOK THAT WAY TO SOME BUT THEN WE'RE ABLE TO SORT OF CUT THIS AREA OFF AND TAKE THAT OUT OF THE PATIENT AND THEN ON THE BACK TABLE, AGAIN WE USE THAT SAME BACK TABLE SET UP, THE FELLOWS HAVE SORT OF DESIGNED THIS REALLY COOL WAY TO HOLD EVERYTHING STILL, AND THEY TIE AS WE DO IN SURGERY, TIE KNOTS DOWN AND MAKE SURE IT STAYS AFFIXED TO THE PLATFORM AND THEN WE HAVE A RUNNER THAT RUNS DOWN TO THE LAB AND BRINGS THIS INTO THEOX GENERATEDDATED PROFUSION CIRCUIT, THIS IS WHAT IT LOOKS LIKE ON THE RIGHT, CAN YOU SEE THERE'S AN OBVIOUS NODULE OR METASTASIS SURROUNDED BY WHAT OTHERWISE WOULD BE NORMAL PEROTONEUM, OKAY. AND SO THE MAINTENANCE OF THIS SYSTEM TOOK US A LONG TIME TO FIGURE OUT. BY US I DON'T MEAN ME, I MEAN IT TOOK THE FELLOWS, THE PARTNERS, MY PARTNERS A LONG TIME TO FIGURE THIS OUT AND SO, WHAT WE REALIZED EARLY ON WAS THAT WE WOULD NEED A SMALL CHAMBER, WE COULDN'T HAVE SOMETHING HUGE BECAUSE THE PLASMA VOLUME WAS TOO MUCH. WE WERE DRAWING TOO MUCH BLOOD FROM PEOPLE AND THAT'S NOT FAIR AND WE WEREN'T GOING TO DO THAT SOY REALIZED WE NEEDED TO SHRINK EVERYTHING DOWN AND THEN WE NEEDED TO HAVE THE PERSTALTIC PUMP BUT WE NEEDED A WAI TO CONTROL THE Ph ANDOX GENERATEDDATION, AND YOU CAN BE THE JUST RUN PURE OXIEN AND SO WE ENDED UP COMING WITH A GAS MIXER AND WE ENDED UP BUYING MULTIPLE GAS MIXERS WHICH ALLOWED US TO HAVE THE OX GENERATED--OXYGEN LEVELS, AND THEY REALIZED THERE WERE ELECTROLYTE ABNORMALITIES AS RESULT OF THE LOSSES SO JAIMINGS HOOKED UP A SYRINGE PUMP TO THE SYSTEM THAT SLOWLY DREVERS WATER AT THE RATE OF BASICALLY TO REPLACE EVABBARATIVE WATER AND TO MAINTAIN ELECTROLYTE LEVELS AS THEY WOULD BE IN THE PERSON ISSUES IN THE PATIENT. SO OUR FIRST QUESTION WAS OKAY, THIS IS COOL, BUT DOES IT ACTUALLY REFLECT WHAT COMES OUT OF THE PERSON? SECONDLY, CAN WE DO THIS ON ANY TUMOR TYPE? AGAIN I THINK THE IMPORTANCE HERE, PARTICULARLY CONSIDERING WHERE WE WORK IS THREEZ RARE TUMORS THAT DON'T HAVE A LOT OF GOOD ANSWERS AND DON'T HAVE A LOT OF OR ANY PRECLINICAL MODEL, THIS WOULD BE THE CASE FOR GASTROINTESTINAL STROMAL FOR EXAMPLE AND WHAT I'M SHOWING YOU HERE IS THAT WE'RE ABLE TO MAINTAIN HISTOLOGY, AND WE'RE ABLE TO MAINTAIN CELL NUMBERS, T-CELLS MACROPHAGES, PROLIFERATION, CONTINUES DURING OUR 4 DAY TIME POINT. WHEN YOU LOOK AT THE TUMOR TRANSCRIPT ORDER OF MICRONSICALLY WHICH IS OF COURSE COMMON NOW DAYS YOU SEE IS WE DO SEE ELEVATIONS IN HYPOXIA, AND YOU KNOW WE DON'T HAVE ANY RED CELLS IN THE SYSTEM, SO WE RAISED THE OXYGEN LEVELS AS HIGH AS WE CAN, WE DON'T ACCEPT ANY THICK TUMORS BECAUSE WE'RE RELYING ON OXYGEN DIFFUSION BUT OTHER THAN THAT THE TUMORS STAY REALLY QUITE AS THEY DID WHEN THEY CAME OUT OF THE PERSON'S BODY AS BEST WE CAN TELL. NOW, WITH THE SYSTEM SORT OF OPTIMIZED THAT 1 OF THE FELLOWS [INDISCERNIBLE] CAME TO US AND SAID, YOU KNOW YOU MIGHT AS WELL--YOU'RE NOT REALLY LOOKING AT THIS IN A WAY THAT YOU COULD. YOU SHOULD LEVERAGE THE ADVANTAGE HERE OTHERWISE YOU'RE SORT OF BEHAVING LIKE THOO CAVE PEOPLE AND ARI BA HAD THIS IDEA THAT WE COULD TAKE THAT PLATFORM OUT OF THAT PROFUSION CIRCUIT AND ARIBA IN CONJUNCTION WITH ENGINEERS REDESIGNED A WAY TO IMAGE THE TUMOR ON AN INVERTED WHITE LIGHT LASER CONFOCAL SCOPE. THIS FIRST DONE ON A MULTIPHOTON SCOPE AND FOW WE DO IT ON A WHITE LIGHT LASER SCOPE AND IT'S A SCREW TYPE MECHANISM SO WE CAN CONTROL THE DEPTH AND THEN ARIBA AND THE TEAM DOES IS THEY INCUBATE WITH ANTIBODIES TO HIGHLIGHT VARIOUS CELL FRACTIONS AND THEN THIS SITS JUST LIKE THIS, AND THEY'VE DESIGNED A STAGE INCUBATOR TO MAINTAIN NIZIO LOGIC PARAMETERS DURING THE ACTUAL VISUALIZATION, SO IT'S ALMOST LIKE WE'RE PUTTING A WINDOW INTO THE TUMORS SO WE CAN THEN REALIZE WHAT'S GOING ON IN REALTIME. TO THE BEST OF MY KNOWLEDGE THIS HAS BEEN DONE WITH ANIMALS BUT I DON'T KNOW IT'S EVER REALLY BEEN DONE WITH HUMANS ON A SCALE LIKE THIS, SO LET ME SHOW YOU THE SORT OF INFORMATION YOU GET AND SO HAD IS A GASTRIC CARCINOMA TO THE PEROTONEUM AND YOU CAN SEE WHAT WE'VE DONE HERE IS LABELED TUMOR CELLS WITH A GREEN CD44 AND WE'VE LABELED IMMUNE CELLS WITH A CD45. COLLAGEN IS BLUE UP HERE IN THE TOP AND YOU CAN SEE THE ACTIVITY OF THESE IMMUNE CELLS NOT NECESSARILY KILLING ANY TUMOR CELLS BUT YOU CAN SEE, THE ACTIVITY AND I CAN TELL YOU NOT ALL TUMORS LOOK LIKE THIS. HERE'S ANOTHER EXAMPLE OF A MESOTHELIOMA ON THE LEFT HERE AND WHAT CAN YOU SEE IS THE TUMORS OVER HERE AND THE ACTIVE IMMUNE CELLS OVER HERE AND THE IMMUNE CELLS ARE IN RED, THIS WOULD BE DESCRIBED AS A COLD NODULE, YOU DON'T SEE MANY IMMUNE CELLS MIXED IN WITH THE TUMOR CELLS. NOW ON OCCASION WHAT WE SEE IS THIS IS A REALLY COOL VIDEO, OVER HERE ON THE RIGHT, I WILL DRAW YOUR ATTENTION TO THE GREEN AGAIN, A CD44 TUMOR CELL AND THE RED IS AN IMMUNE CELL AND YOU CAN SEE THIS IS AN ENDOGENOUS NO DRUGS ADDED AND THERE'S AN IMMUNE CELL THAT RUINS RIGHT UP AGAINST THESE TUMOR CELLS AND DOCKS TZ ON THIS TUMOR CELL AND BEGINS KILLING IT. AND SO THIS SORT OF STUFF, YOU WOULDN'T OTHERWISE KNOW THAT THIS SORT OF HAPPENS WITHOUT DRUGS ON A SORT OF CONTINUAL BASIS BUT IT APPEARS TO IN CERTAIN TUMORS AND NOT IN OTHERS. AND THIS WAS REALLY AN ENLIGHTENING PIECE OF INFORMATION AND THERE'S A LOT OF CONSTERNATION ABOUT WHO'S GOING TO RESPOND TO IMMUNOTHERAPY AND WHO SUBJECT AND HOW ARE WE GOING TO DECIDE WHO TO GIVE THIS TO AND NOT, AND THERE ISN'T A PERFECT WAY LONG AND SHORT. I DON'T REALLY SRO THE TIME TO GO THROUGH ALL THE LITERATURE BUT WE'RE ABLE TO ADD ANOTHER PARAMETER. NOW WHETHER IT WILL BE USEFUL OR NOT, I DON'T KNOW BUT WE'RE CLEARLY ABLE TO ADD A DYNAMIC METRIC, ARIBA HAS THAT PREVIOUSLY HAS NOT BEEN ACCOUNTED FOR. AND I THINK THAT POINT IS MADE BEST BY EXAMINING THESE 2 MOVIES SIDE BY SIDE. YOU CAN SEE THE 1 ON THE LEFT METASTATIC COLORECTAL ADEN O CARCINOMA, VERY ACTIVE IPT GREATERUNE CELLS, THOSE CELLS RUNNING,A ROUND IN RED, LOOK LIKE ANTS RUNNING AROUND OR SOMETHING LIKE THAT, VERY ACTIVE IMMUNE SYSTEM IN THIS TUMOR WHEREAS THIS GASTROINTESTINAL STROMAL TUMOR VERY QUIESCENT, DON'T SEE A LOST MOVEMENT, MAYBE A LITTLE BIT BUT REALLY NOT A LOT. NOW THE TASK IS ON US TO DETERMINE WHETHER THIS MEANS ANYTHING BUT I THINK IT WILL BE A VALUABLE METRIC MOVING FORWARD. ARIBA THEN ASKED THE QUESTION, THAT'S PRETTY INTERESTING, HOW LONG CAN WE DO THIS? HOW LONG CAN WE PUT OUR CAMERA INTO THIS TUMOR AND REALLY TAKE A LOOK? THE ANSWER IS WITHOUT DETRIMENT TO THE IMMUNE CELLS AND WE'VE DETERMINED DETRIMENT IN THIS EXPERIMENT BY LOSS OF MOVEMENT AND WE CAN DO IT FOR UP TO 8 HOURS AND THAT'S REALLY COOL BECAUSE THAT SUGGESTS CAN YOU PUT A DRUG INTO THE SYSTEM AND REALLY WATCH BEFORE AND AFTER DEPENDING ON THE DRUG AND DEPENDING ON WHAT YOU THINK THE KINETICS ARE, BUT THIS ALLOWS YOU YOU TO LOOK BEFORE AND AFTER AND THAT'S REALLY QUITE COOL. NEXT ARIBA AND THE TEAM ASKED A DIFFERENT QUESTION, WHAT IF YOU DO THIS NOT NECESSARILY FOR A VERY LONG PERIOD OF TIME BUT WHAT IF YOU DID THIS OVER CONSECUTIVE DAYS SUCH THAT YOU COULD TAKE THE SNAPSHOTS IN A DIFFERENT WAY RATHER THAN 1 LONG CONTINUOUS MOVIE COULD YOU DO THIS ON VARIOUS DAYS AND THE ANSWER IS YES, YOU CAN, CAN YOU DO IT FOR 2 DAYS AND YOU CAN SEE WITHOUT--CAN YOU SEE THE CELLS STILL REMAIN HAPPY AND STILL MOVE. AGAIN RED MARKS THE IMMUNE CELLS WITH THE CD45 MARKER SO WHAT WE BEGIN TO REALIZE IS WE'VE GOT A VERY COOL TOOL TO BEGIN TO EVALUATE HUMAN TUMORS IN A WAY THAT IS SORT OF HARD TO DO IN A PERSON, HARD TO DO IN A MOUSE, I CAN TELL YOU BECAUSE I'VE TRIED AND HARD TO DO IN AND PROBABLY IMPOSSIBLE TO DO IN ANY OTHER MEANINGFUL WAY. SO, NEXT, YOU KNOW ARIBA AND THE TEAM SAID WELL, OKAY, WE CAN ONLY DO A COUPLE PARAMETERS LIVE, BUT WHAT IF WE THEN BEGIN TO MULTIPLEX ON TOP OF THAT USING VARIOUS TECHNIQUES AND THAT'S EXACTLY WHAT WAS DONE HERE. SO YOU CAN--YOU KNOW USE THE RED AND GREEN LIVE, BUT AFTER THAT WE COULD FIX IT, SECTION IT SUCH THAT WE COULD ORIENT OURSELVES BACK TO WHERE THE LIVE IMAGING WAS AND THEN REALLY GAIN A LOT OF INFORMATION AND IF--IF WE DID THAT I WILL SKIP FORWARD, IF WE DID THAT WE COULD REALLY BEGIN TO UNDERSTAND THE WHOLE 3 DIMENSIONAL PICTURE, REMEMBER, YOU CAN ONLY SEE WHAT RIEWR LOOKING FOR BUT IN THIS SCENARIO, YOU WE CAN SEE LIVE ELEMENTS AND THEN WE CAN BEGIN TO UNDERSTAND THE REAL COMPLEXITY OF TUMORS, AFTER WE'VE ACQUIRED THE DYNAMIC PARTS OF THE IMAGING. NOW MARTHA CAME TO THE LAB AND SAID, WELL, HAVE YOU A COOL SYSTEM, THAT'S TRUE, NO 1 CAN DENY THIS BUT YOU HAVE A LIMITATION AND THAT LIMITATION IS, YOU CERTAINLY HAVE AN INTACT TUMOR MICROENVIRONMENT, AND, THAT'S COOL BUT HOW DO YOU MODEL ANY NEW CELLS WHEN YOU COME INTO THE TUMOR, AND SO EXAMPLE WOULD BE HOW DO YOU MODEL, IMMUNE CELL RECRUITMENT AND YOU DON'T HAVE A WAY OF DOING THAT AND SO WHAT MARTHA DID, MARTHA REELZED WE WERE DRAWING A BUNCH OF BLOOD, BLOOD FROM PATIENTS AND THEN WE WERE SIMPLY THROWING AWAY THE BUFFING OR THE BPMCs, AND MARTHA CLICKED THEM INSTEAD OF THROWING THEM AWAY AND BEGAN TO LABEL THEM WITH A TRACKING DIE. AND SHE DEVELOPED WITH A TEAM OF ENGINEERS A WAY OF INJECTING THESE LABELED CELLS, NOT INTO THE TUMOR, THAT WOULD BE SORT OF--I DON'T KNOW IF THAT WOULD BE REALISTIC BUT MARTHA DEVELOPED A WAY TO INJECT THOSE CELLS INTO THE P EROTONEUM AJAIZENT OR AWAY FROM THE TUMOR, IT'S A FANCY SET UP AND A VERY FANCY GONIOMETER WITH A SENSITIVE INJECTOR AND SO MARTHA DEVELOPED THIS TECHNIQUE AND I'M GOING TO SHOW YOU WHAT THIS LOOKS LIKE, IF THE SLIDES WILL ADVANCE. HERE WE GO SO WHEN MARTHA INJECTS THOSE CELLS, SHE SEES THEM AS SORT OF ROUND IN THE BEGINNING BUT OVER A PERIOD OF ABOUT 3-4 HOURS, THEY BEGIN TO ELONGATE AND THEY ACTUALLY MOVE ALONG FIBERS OF THE NORMAL MESOTHELIUM WHICH IS REALLY COOL AND THE QUESTION BECOMES, IS THIS PURPOSEFUL MOVEMENT OR IS IT JUST SORT OF MOVEMENT? AND THE QUESTION BECOMES DOES IT GET INTO THE TUMOR AND IN FACT, WHAT WE'VE BEEN ABLE TO TO SHOW, WHAT MARTHA'S BEEN ABLE TO SHOW ALONG WITH ARIBA AND THE REST OF THE TEAM, THAT THOSE OVER A PERIOD OF A COUPLE OF DAYS, THOSE INJECTED PBMC'S LABELED FEAR IN GREEN, THEY ALSO ARE IMMUNE CELLS OF COURSE SO THEY HAVE A RED, GREEN, AND RED LABEL. THOSE ARE FOUND INSIDE THE TUMOR AT THE END OF A 2 DAY RUN AND THEY INTERACT WITH AN EVEN KILL TUMOR CELL AND I WILL SHOW YOU THAT HERE. WHAT YOU CAN SEE HERE IS 1 OF THOSE GREEN AND RED CELLS, HERE IS A CYAN WHICH MARKETS A TUMOR CELL AND YOU CAN TRACK THIS OVER TIME, I'VE TAKEN IT OUT OF A MOVIE FORMAT JUST TO MAKE IT EASIER TO SEE AND WHAT YOU CAN SEE IS THIS CELL IS NOW INTIMATELY ASSOCIATE WIDE THAT TUMOR CELL. AND THAT WILL ULTIMATELY RESULT IN THAT TUMOR CELL DYING. OKAY, I'VE SHOWED YOU THE FACT THAT MY PARTNERS OVER THE LAST SEVERAL 4 OR 5 YEARS, HAVE DEVELOPED THESE REALLY COOL TOOLS TO BE ABLE TO INVESTIGATE DRUGS IN AN OTHERWISE UNFETTERED FLAT FORM AND NOW I WILL SHOW YOU HOW WE WILL USE THESE TOOLS, OKAY? SO, EMILY [INDISCERNIBLE] WAS HEAVILY INVOLVED IN THE SMART SYSTEM AND OPTIMIZING IT BUT SHE STARTED THESE EXPERIMENTS BY ADDING THE TRIED AND TRUE ILTWORKS THE OLD NIH IL2 AND HERE WE GO, AND WHAT 'EM ILLEGALS SHOWED THAT WAS THAT AFTER BEING IN THE SYSTEM FOR 4 DAYS, YOU CAN DUMP INTERLEUKIN 2 ON TO THE SYSTEM AND YOU CAN SEE THE IMMUNE CELLS IN THE SYSTEM RESPOND BY MOVING AND INCREASING THEIR VELOCITY AND THAT'S ACTUALLY MAPPED OUT HERE. AND SO THIS WAS OUR FIRST SORT OF REAL DATA THAT YOU CAN ADD DRUGS INTO THE SYSTEM AND THE IMMUNE CELLS WILL RESPOND TO IT, NOW EMILY, WAS INTERESTED IN IMMUNOTHERAPY AND SO WE WANTED TO GET A DRUG THAT WAS BEING USED CLINICALLY AT THE CLINICAL CENTER SO EMILY CONVINCED SOME OF OUR FRIENDS FROM THE NOW CENTER FOR IMMUNO ONCOLOGY TO LET US TRY M7824, NOW THIS IS A PBL 1 BI FUNCTIONAL TGF BETA TRAPPED MOLECULE. OKAY, AND WHAT WE ULTIMATELY SAW WAS WHEN WE GAVE THE DRUG WE COULD IN CERTAIN PATIENTS SEE, I WON'T GO THROUGH THIS IN ENTIRETY BUT WE COULD SEE CELL KILLING, WE COULD SEE CLUSTERING OF CD8 CELLS SEQUESTERED TO CERTAIN AREAS, THESE ARE AREAS THAT CO INSIDED WITH CELL KILLING BY TUNNEL STAIN WHICH WAS REALLY COOL FOR US. NOW EMILY DID SIGNED, AND THOUGHT ABOUT AND DESIGNED THIS EXPERIMENT AND SO, WE TOOK SEVERAL PATIENTS WHO ACTUALLY RECEIVED THE DRUG ON A STUDY AND WE ENDED UP OPERATING ON THEM. AND WE USED THEIR TUMOR IN THE SMART SYSTEM AND THEN WE LOOKED AT WHAT HAPPENED TO THEIR TUMOR BECAUSE WE ALREADY KNEW WHAT HAPPENED TO THEM IN REAL LIFE. AND THEN WE TOOK A SEPARATE SMART COHORT, THESE ARE PATIENTS WHO NEVER SAW THE DRUG, AND WE GAVE THEM THE DRUG IN THE SMART SYSTEM AND THEN WE LOOKED TO SEE WHAT HAPPENED, JUST SO SHOW THE CLINICAL RESPONDERS AND NONRESPONDERS. SO THE CLINICAL RESPONDERS IS AN INTERESTING STORY. HOW WOULD YOU GET A TUMOR THAT RESPONDED TO A DRUG AND AT THE END OF THE TIME WOULDN'T IT JUST BE RESIDUAL CELLS, THAT WOULD BE TRUE BUT AS IT TURNS OUT THAT PATIENT RECEIVED TOXICITY FROM THE DRUG AND SHE WOULD COME OFF THE DRUG AND THE TUMOR WOULD GROW AND THEN SHE WOULD DP BACK ON THE DRUG AND THE TUMOR WOULD SHRINK AND THEN SHE WOULD GET THE DRUG AGAIN AND SO ON AND SO FORTH AND I ENDED UP OPERATING ON HER SO SHE WAS SOMEBODY WHO HAD TUMOR WE KNEW WOULD BE RESPONSIVE TO THE DRUG, SHE WAS OUR TRUE POSITIVE AND THEN THERE WERE PEOPLE WHO GOT THE DRUG AND NOTHING APPARENTLY OSTENSIBLY HAPPENED TO THE TUMOR ON RADIO GRAPHS WHICH IS OUR GOLD STANDARD AND WE LOOKEDDA THE SINGLE PATIENT WHO RESPONDED VERY WELL, IS THAT PATIENT THAT INCLUDED DAY 0 HERE AND THIS IS A 2 DAY EXPERIENCE, I INCLUDED DAY 0 JUST TO SHOW YOU NOTHING REALLY HAPPENED BETWEEN THE CONTROL IN DAY ANSWER BUT WHAT WE SEE IS ACTIVATED NATURAL KILLER CELLS, WE SEE ACTIVATED CD8 CELLS, WE SEE PROLIFERATING CD45 POSITIVE IMMUNE CELLS, INCREASED CASPACE 3, SO CELLS ARE DYING, WE SEE DECREASED PDL 1 STAINING MEMBER BECAUSE THIS DRUG BINDS TO PDL MASKING THE EPITOPE WE WOULD GUESS SO THIS IS WHAT IT LOOKS LIKE WHEN SOMEBODY RESPONDS TO THE DRUG. AND SO, I WILL SHOW YOU THE NATURAL KILLER CELL ACTIVATION AND WHEN WE LOOK AT EMILY'S TEST COHORT, SOME OF THESE PATIENTS LOOK VERY SIMILAR TO WHAT HAPPENED TO THE PERSON WHO ACTUALLY GOT THE DRUG AND RESPONDED TO IT AND HERE'S THE CD8 POSITIVE, AGAIN, WE SEE THAT RELATIONSHIP WITH 1 OR MAYBE 2 OF THE PATIENTS WHERE THEY LOOK LIKE THE PERSON WHO RESPONDED TO THE DRUG. HERE'S THE DATA FOR KI67. SAME THING IS TRUE HERE, HERE'S THE DAILY BASIS THEA FROM PDL 1 AND THE CULMINATION OF THIS EXPERIMENT IS NOT TO SAY THAT, YOU KNOW THIS PERSON RESPONDED TO THE DRUG. EMILY WOULD TELL YOU THAT THIS PERSON--WE OUTTO THINK ABOUT T-REGGAGING THIS PATIENT TO THORS STUDY SHOULD THE DISEASE COME BACK AFTER WE OPERATED ON THEM. AND MUCH TO MY DISPLAY MOST OF THE TIME, PATIENTS WITH VERY AGGRESSIVE DISEASE END UP HAVING RECURRENCE OF DISEASE SO I THINK OF THIS EXPERIMENT AS A VERY GOOD DEMONSTRATION THAT THIS CAN BE USED AS A TRIAGE TOOL TO VARIOUS STUDIES IN THE CLINICAL CENTER. OKAY, WE'RE MOVING ALONG WIGHT A BIT HERE WE'RE OKAY ON TIME BUT I'M RUNNING SHORT SO I WILL SHOW THIS DATA. NOW WHEN I WAS A FELLOW--I WILL SHOW THIS DATA BECAUSE I WANT TO HIGHLIGHT THE CONTRIBUTIONS OF 2 PEOPLE WHO WORKED REALLY HARD ON A SEPARATE PART OF THE LAB. AND THEN ULTIMATELY UTILIZE THE SYSTEM TO REALLY--FOR REALLY A BENCH TO BEDSIDE EFFORT. SO WHEN I WAS A FELLOW AT SLOAN KETTERRING, 1 THING I DID WAS A COLLECTED, WELL WAS THERE WAS A BANK OF BILE ON PATIENTS AND WE COLLECTED EXOSTUDIES OF MULTIPLE ENDOCRINES FROM THIS BILE AND 1 OF THE THOUGHTS WAS MAYBE WE COULD LEARN SOMETHING ABOUT CO LANCHIAL CARCINOMA CANCER OF THE BILE DUCTS AND WE LOOK AT THE EXOSTUDIES OF MULTIPLE ENDOCRINES AND THE PROTEIN IN THE EXOSTUDIES OF MULTIPLE ENDOCRINES KIND OF HARD TO DO SINGLE CELL MASS SPECT TROMETRY OR PROTEOMICS SPECIAL SO 1 THING WE REALIZED WAS THERE A HIGH LEVEL OF SOMETHING CALLED EXPORT AND 7, I CAME TO THE NIH WITH THIS DATA, I AWLTZ KNEW IT WAS VERY INTERESTING--ALWAYS KNEW IT WAS VERY INTERESTING, IT WASN'T ALL PATIENTS, IT WAS MOST, ABOUT A FRACTION, ABOUT A THIRD OF THEM BUT WHEN IT WAS--WHEN XPO7, WHEN WE LOOK AT THE STAINING THIS WAS DONE AGAIN BEFORE I LEFT AND BEFORE I CAME HERE, WHAT WE SAW WAS THAT WAS THERE CYTOPLASMIC STAIN NOTHING THE CANCER CELLS WHICH WAS SORT OF WEIRD AND AGAIN WHEN I TOLD YOU BEFORE THAT SAM AND MIKE JOINED THE LAB, MY FIRST YEAR HERE IN JULY OF 2017 AND I ACTUALLY TOOK 3 THAT YEAR AND [INDISCERNIBLE] AND I SAT THE 3 OF THEM DOWN, I DON'T KNOW IF I CAN TAKE 3 OF YOU, AND THEY CAME BACK TO ME LATER IN THE DAY, THEY SAID NO, WE WANT TO DO THIS AND I SAID, WELL WHO AM I TO TALK YOU OUT OF IT SO REED WORKED INCREDIBLY HARD ON THIS AND THE FIRST THING REED DID WAS HE GOT A TISSUE MICROARRAY FROM STEVE YOU HADET HERE AND STEVE STAINED THE TISSUE MICROARRAY AND WE VALIDATED THIS ON AN INDEPENDENT COHORT, THAT THERE'S A FRACTION OF THESE PATIENTS WITH CO LANCHIAL CARCINOMA THAT HAVE THIS EXVIVO STAIN NOTHING THE CYTOPLASM AND LOW AND BEHOLD IT RESULTS IN WORSE SURVIVAL AND THAT IS TRUE ON A MULTIVALID AND RELIABLE YABT ANALYSIS SO WHATEVER THIS IS, IT'S A MARKER OF AGGRESSIVE DISEASE. NOW REED DID A LOT OF EXPERIMENTS BUT HE FIGURED OUT WAS FROM USING TUMOR ORGANIZATIONS RANNOIDS WHAT HE FIGURED OUT WAS THAT WHEN YOU DID A NEW CLE O PLASMIC SEPARATION AND AN EXPERIMENT FROM THE CYTOPLASM HE PULLED DOWN SOMETHING CALLED SLK, HE THEN DID THE OPPOSITE EXPERIMENT WHERE HE PULLED DOWN SLK AND HE GOT XPO7. AND WHEN YOU DO THIS COMPUTATIONALLY THESE 2 MOLECULES FIT TOGETHER VERY WELL, SO HMM, A KINASE, THAT'S INTERESTING AND YOU CAN INHIBIT KINASES SO WE DID THIS WITH SHORT HAIR PINS IN THE BEGINNING AND WE REALIZED THAT IN AN ORTHOTOPIC TUMOR INJECTION MODEL THAT YOU ACTUALLY INHIBIT TUMOR FORMATION AND IT FORMS BUT IT'S SMALL BUT REALLY COOL IS IT LOOKS WAY DIFFERENT THAN A FORMAL TUMOR, IT'S NOT JUST A SMALL TUMOR, IT HAS A CYSTIC APPEARANCE, THERE'S A LOT OF DEGENERATING CELLS, THERE WASN'T A LOT OF TUMOR INVADING INTO THE SORT EVER NORMAL LIVER ARCHITECTURE THAT WE ALWAYS SEE WITH THIS DISEASE. AND THEN TOSSIN JOINED THE LAB SEVERAL YEARS AGO AND TOSSIN HAD EXPERIENCE WITH SIGNALING AND HE SAID, WELL, YOU CERTAINLY CAN'T GIVE PEOPLE SHORT HAIR PINS BUT CAN YOU DO IS GIVE PEOPLE KINASE INHIBITORS. WELL, THERE IS NO KINASE INHIBITOR TO SLK SO TOSSEN WORKED WITH OUR FRIENDS AT CAPER AND HE CAME UP WITH SEVERAL DRUGS HE THOUGHT MAYBE COULD WORK AND AND HE RAN THIS EARLY EXPERIMENT WHERE HE SHOWED THAT 1 OF THESE DRUGS, RESULT IN SUBSTANTIAL TUMOR REGRESSION, NOT JUST PREVENTATIVE TUMOR FROM GROWING, HE LET THEM GROW AND TREATED THEM AND HERE'S THE WATER FALL PLOT AND HE SAW SHRINKAGE OF THESE TUMORS. NOW TOSSIN DID A TON OF WORK, IT'S OUTSIDE THE SCOPE OF THIS TALK BUT TOSSIN REALLY PROVED THAT THAT DRUG TIVOZANIB BINDS AND PUSHING UP THE REGION AND BLOCKING THE KINASE FUNCTION. HE DID THIS, I'M SHOWING YOU HERE BECAUSE IT LOOKS THE COOLEST BUT HE DID THIS--USING AND CRYSTALLIZING SLK WITH [INDISCERNIBLE] DRUGS AND CRYSTALLIZED UNDER HIS WATCH, HE ALSO DID A NUMBER OF EXPERIMENTS, KINASE DEAD CONSTRUCTS HE HAS DRUG RESIST ABT CONSTRUCTS AND THE DRUG COMBINED, SO HE DID A LOT OF WORK TO PROVE THIS IS IN FACT, HAPPENING THEN HE SAID OKAY, WE NEED TO GET AHOLD OF PDXs AND WE DIDN'T HAVE PDXs, THE NIH DOESN'T HAVE ANY PDXs BUT WE BOUGHT THEM FROM A VENDOR AND WE CHECKED THISEM AND LOW AND BEHOLD THEY ALL HAD EXPRESSION IN THE CYTOPLASM AND WHEN WE TREAT WITH THE SINGLE DRUG TIVOZANIB, WE SEE QUICKLY THAT IT DOESN'T GROW AT ALL, IT STAYS AND SHRINKS AND THIS PDX GREW QUICKER AND IT EXPERIMENT IS TILL ONGOING, THEY BOTH ARE REALLY, BUT THIS DRUG LOOKS LIKE IT WORKS VERY WELL'RE XPO7 EXPRESSING FILLAGEIO CARCINOMA NOW TOSSIN WANTED TO TAKE THIS A STEP FURTHER. I WILL TAKE IT BACK FULL CIRCLE AND SHOW THAT TOSSEN THEN USED THIS DATA AND TREATED 2 PATIENTS IN THE SMART SYSTEM, FIRST PATIENT WAS ON THE LEFT HERE THIS, IS PATIENT LABELED A, THIS IS AN XPO7 NEGATIVE CO LANCHIAL CARCINOMA, WHEN YOU GIVE THE DRUG INTO THE SYSTEM, IT'S A 4 DAY EXPERIMENT WHAT YOU SEE IS NOT A WHOLE LOT TO BE FOUND TOTALLY HONEST WE DON'T SEE A MUCH INCREASE IN CASPACE 3, TUNNEL STAINING DEPECTED GRAPHICALLY HERE, CONTRAST THAT TO THE PATIENT WHO HAD XPO7 AND THE CYTOPLASM AS SHOWN BY THE GROUND STAIN HERE AND WHAT HAPPENED WHEN WE GAVE TIVOZANIB FOR 4 DAYS YOU CAN SEE TUMOR DEATH BY DAY 3 AND TUNNEL STAINING AND YOU CAN SEE THAT QUANTIFIED HERE AND YOU CAN SEE A HUGE AMOUNT OF CELL DEATH ASSOCIATED WITH THIS DRUG. NOW, TOSSEN AND I THEN SAT AND WE WERE VERY IMPRESSED BY ALL THIS DATA. WE APPROACHED THIS COMPANY AND SAID WE WANT THIS DRUG TO RUN IN PATIENT SAYS, THIS WOULD BE A FIRST EVER CO LANCHIAL CARCINOMA ANDY WOO WE WROTE THIS TRIAL TOGETHER AND I'M PROUD TO SAY WE HAVE NOW TREATED OUR SECOND PATIENT ON STUDY, WE DON'T ARE RESULTS YET, THEY ARE BEING TREATED WE HAVEN'T DONE ANY EVALUATION YET BUT WE'VE TREATED 2 PATIENTS ON STUDY, AND THIS IS A TRUE BENCH TO BEDSIDE MISSION, MISSION ACCOMPLISHED, NOW OF COURSE IT HAS TO WORK OTHERWISE IT DOESN'T MATTER BUT WE'RE HOPE EMPLOY. OKAY, I WANT TO END WITH AGAIN A THANK YOU. I MEANT TO HIGHLIGHT EVERYBODY'S CONTRIBUTIONS AND I DIDN'T GET A CHANCE TO GO THROUGH ALL OF THE NEWER FELLOWS IN THE LAB BUT CARRY RYAN'S DOING SOMETHING COOL, SHE FIGURED OUT A WEB CONNECTED AND THEY'RE GOING TO FIGURE THAT OUT, LAILA IS, WOOING ON SOMETHING NEAR AND DAILY BASISSER TO MY HEART WHICH IS IDENTIFYING CELLS THAT YOU CANNOT OTHERWISE SEE IN MICROMETASTASIS AND LARGE PIECES OF LIVER, STEPHANIE GREGORY WILL IS WORKING WITH ANDREW BLAKELY AND WE'RE LOOKING TO SEE IF WE CAN AND DECIDE WHICH DRUGS WE SHOULD GIVE PATIENTS RIGHT NOW IT'S A GUESS, STEPHANIE STANDS TO MAKE A BIG CONTRIBUTION THERE, I JUST WANT TO BE EVERYBODY SORT OF CAME TOGETHER AND EVERYBODY CONTRIBUTED AND IT HAS TRULY BEEN MY PLEASURE OVER THESE LAST 5 OR 6 YEARS TO WORK WITH ALL OF THESE PARTNERS THAT I'VE HAD. --WORKED REALLY, REALLY HARD TO DEVELOP THESE COOL IMAGING THINGS YOU JUST SAW, ANDREW BLAKELY AND JEREMY DAVIS ARE MY SURGERY PARTNERS AND OPERATE ON THESE PATIENTS WITH ME. AND WE WOULDN'T--NONE OF THIS WOULD BE POSSIBLE IF WE DIDN'T DO A VERY GOOD JOB FOR PATIENTS AND I'M VERY PROUD OF THE WAY WE TREAT PATIENTS AND HOW WE TAKE CARE OF THEM. AND VERY PROUD OF EVERYBODY IN THE OPERATING RADIO AM AND EVERYBODY DOES WHAT THEY CAN AND THEY TAKE CARE OF THE PATIENTS AND THEY MAKE THINGS HAPPEN. DR. CLIENER WE WOULD BE LOST WITHOUT HIM, HE REVIEWS ALL THESE SORT OF HISTOLOGY FOR US ON ALL OF THESE RUNS, AND I WOULD SAY PROBABLY THE PERSON I DIDN'T MENTION YOU GO PROBABLY DESERVES NOR CREDIT THAN I DO FOR SURE AND TOM AND HIS GROUP. THEY ARE THE ENGINEERS THAT HAVE WORKED BEHIND THE SCENES REALLY CREATE ALL OF THESE THINGS, SO OUR IDEAS CAME TO FRUITION BY TOM, JOHN, MARCI, RANDY, THE GUYS OVER THERE AND THEY REALLY HAVE DONE AN EXCELLENT JOB AND CO INVEBTORS ON ALL THE PATENTS. SO WITH THAT, I WOULD LIKE TO END AND TAKE ANY QUESTIONS. >> DR. HERNçNDEZ, OKAY, SO IMIE FIRST OF ALL I WANT TO THANK YOU FOR SHARING YOUR ABSOLUTELY FASCINATING WORK AND CONGRATULATIONS ON ALL YOUR PROGRESS. WE LOOK FORWARD TO SEEING WHAT YOU WILL ACCOMPLISH IN THE FUTURE, I THINK WHAT'S MOST IMPORTANT AND STANDS OUT TO ME IS YOU WERE SELECTED AS OUR DISTINGUISHED CLINICAL TEACHER AT EVERY STEP IN THE PROGRESS OF YOUR RESEARCH, YOU GIVE SO MUCH CREDIT TO YOUR FELLOWS WHO WOULD BRING LIGHT AND INSIGHTS INTO PROBLEMS THAT WERE ENCOUNTERED WHILE YOU MENTORED THEIR SOLUTIONS THAT THEY SUGGESTED BUT, YOU KNOW IT'S NOT LOST ON US THAT IT IS YOUR OWN INSIGHTS AND THAT HAVE GUIDED TOWARD THESE SOLUTIONS. YOU'RE OBVIOUSLY A VERY HIGHLY RESPECTED METROPOLITANNOR AND LAUNCHED MANY CAREERS HERE FOR NEW PHYSICIAN SCIENTISTS SPECIFICALLY SURGEON SCIENTISTS AND AGAIN CONGRATULATIONS ON YOUR WELL-DESERVING OF THE CLINICAL TEACHER AWARD AND SO CONGRATULATIONS FOR THAT AND THIS WONDERFUL TALK. SO WE HAVE TIME FOR--THERE'S A COUPLE QUESTIONS HERE. LET'S SEE HERE, TO START, SO YOUR SYSTEM LOOKEDDA THE VARIOUS TUMORS IS THERE A TYPE OF TUMORROR THAT APPEARS TO BE A BEST CANDAD FOR BEING STUDIED IN YOUR ALAN SYSTEM SPECIFICALLY? >> YEAH, SO THEA WILL AN SYSTEM IS 1 THAT PROABT DOESN'T MATTER AS MUCH I THINK THAT WE HAVEN'T DONE IT ENOUGH TO ANSWER THAT QUESTION, BUT I THINK I WILL ANSWER THAT USING THE SMART SYSTEM, SO, THAT SYSTEM THE MORE AGGRESSIVE THE TUMOR, THE EASIER IT IS. AND SO, TUMORS THAT SORT OF ARE SORT OF SOFT AND HAVE A LOT OF NECROSIS IN THE MIDDLE, THOSE TEND TO BE MORE DIFFICULT FOR US--BUT THE PATIENT HAS DEVELOPED AND KNEW IT WOULD BE FAIRLY AGGRESSIVE AND ONCE THAT HAPPENS THE TUMORS STAY FAIRLY VIABLE, THE ADVANTAGE OF THE ALLEN SYSTEM IS WE DON'T GO ANYWHERE NEAR THE TUMOR, I USE THE INFLOW AND OUTFLOW KNOWLEDGE OF THE LIVER AND INFLOW AND OUTFLOW VESSELS AND THAT TENDINGS TO STAY FAIRLY HAPPY AND YOU WOULD MENTION THE MOST DIFFICULT PART OF THAT SYSTEM IS KEEPING THE LIVER HAPPY, THE LIVER'S NORMAL TISSUE, THE NORMAL TISSUE NOT REALLY MEANT TO BE LIVING LIKE THIS. BUT A TOMB OAR TENDS TO DO JUST FINE. SO I THINK, YOU KNOW THAT THE ALAN SYSTEM IS GOING TO BE--IT'S GOING TO WORK FOR ANYBODY WHO HAS THE METASTASIS IN THE RIGHT PLACE OR IS UNDERGOING A THERAPEUTIC METRICS TAFTSECTOMY AND THAT'S NOT EVERYBODY I OPERATE ON, IT'S A FRACTION BUT TUMOR HAS TO BE IN THE RIGHT LO XAIGZ AND I HAVE TO FEEL LIKE IT'S THE RIGHT THING TO DO FOR THE PATIENT BUT I DON'T THINK THE TYPE OF TUMOR IS GOING TO--I THINK IT'S ALL GOING TO WORK OUT OKAY. I DON'T THINK THAT'S GOING TO BE DETRIMENTAL DEPENDING ON ACROSS VARIOUS TUMOR TYPES, OBVIOUSLY WE HAVE TO PROVE THAT BUT THAT'S MY FEELING. >> THANK YOU. OKAY, LET'S SEE HERE 1 OTHER QUESTION. IT'S EXCITING HOW THE SMART SYSTEM ALLOWS FOR DIRECT EVALUATION TOZINIB IN THE EFFECT OF PATIENTS WHO INSIGHTS HAS YOUR SYSTEM REVEALED TO TUMOR BIOLOGY THAT MAY OFFER THAT OTHER NEXT GREAT STEPS IN THERAPEUTICS? >> SO WHAT I THINK, YOU KNOW, I WOULD SAY, I WILL ANSWER THAT IN THE FOLLOWING WAY, SO, WHEN YOU LOOK AT WHAT HAPPENS WHEN YOU GIVE A DRUG THAT KILLS A LOT OF TUMOR CELLS, THEY DON'T ALL DIE, AND THAT'S SORT OF WHAT WE OTHERWISE KNOW TO BE TRUE IN PATIENTS. YOU DON'T SEE THESE DRUGS MELT AWAY ALL THE TUMOR AND SO, THE HETEROGENERATED AITY IS REALLY, REALLY CAPTURED HERE SO THIS ISN'T AN ISOLATED CELL POPULATION LIKE AN ORGANOID POPULATION WHERE THEY'RE PROBABLY ALL LIKELY TO RESPOND OR NOT, THIS CAPTURES ALL THE HETEROGENERATED AITY AND SO THAT'S A VERY ENLIGHTENING THING THAT YOU REALIZE THERE ARE POCKETS OF TUMOR CELLS THAT APPEAR TO NOT RESPOND AT ALL, THE OTHER THING THAT'S SUPER INSIGHTFUL THAT WE COME TO REALIZE IS YOU SEE AREAS WHERE IMMUNE CELLS ARE KILLING TUMOR CELLS AND THAT IMMUNE SYSTEMUNE CELL COULD HAVE WALKED RIGHT BY 10 TUMOR CELLS AND BE TOTALLY UNBOTHERRED BY THEIR PRESENCE, SO WE'RE ABLE TO VISUALIZE THESE PROCESSES, NOW WE NEED TO UNDERSTAND THEM AND SO WE'RE WORKING ON THAT, BUT THESE SORT OF THINGS THAT THIS CONCEPT THAT SOMETHING WORKS OR DOESN'T, BLACK AND WHITE IT'S NOT REALITY. REALITY IS THAT SOME OF THE TUMOR IS ULTIMATELY KILLED BY THESE DRUGS THAT WORK OR NOT AND SOME ISN'T. AND REMEMBER, THERE'S A DISCREPANCY BETWEEN CLINICALLY WORKING AND NOT, STUFF'S GOT TO SHRINK, NORMAL TISSUE HAS TO GROW IN AND IT HAS TO BE MEASURABLE BUT WHAT'S HAPPENING BELOW THAT IS A VERY COMPLICATED THING AND I THINK IT'S SUPER ENLIGHTENING TO WATCH THESE THINGS. >> WE'RE UP ON THE HOUR AND THAT'S ALL THE QUESTIONS WE SEE. IF I GET ANY MORE QUESTIONS I WILL CERTAINLY REPORT THEM TO YOU FOR ANSWERINGMENT BUT AGAIN I WANT TO SAY THANK YOU FOR THIS ENLIGHTENING AND SUCK SETIONFUL TALK AND CONGRATULATIONS AGAIN FOR BEING NAMED THE DISTINGUISHED CLINICAL TEACHER AWARDEE, CLEARLY, A HIGHLY QUALIFIED APPLICANT AND I THINK OF ANYONE WHO'S MORE DESERVING AND FINALLY I WANT TO THANK THE DECKER FAMILY FOR SUPPORTING THIS LECTURE AND FOR THE GENEROUS SUPPORT THAT YOU'VE GIVEN US AS WELL AS FNIH, THANK YOU VERY MUCH AND EVERYBODY HAVE A WONDERFUL AFTERNOON.