SO, I'M GOING TO GET STARTED BECAUSE SOUNDS LIKE YOU GUYS ONLY HAVE AN HOUR BEFORE YOU HAVE TO GET UP THE HILL SO I DON'T WANT TO BE LATE. LIKE I SAID I'LL BE PRETTY BRIEF. I WILL ASK ANY OF MY COLLEAGUES WHO HAVE BEEN IN THIS SINCE THE BEGINNING AS WELL TO CHIME IN. I THOUGHT I WOULD JUST BE SORT OF GIVE YOU AN IDEA OF WHERE WE HAVE -- WHAT WE'VE LEARNED SO FAR. WHAT OUR STATE OF KNOWLEDGE IS. SO I'LL TALK ABOUT WHAT WE KNOW ABOUT PEDIATRIC GIST IS THAT IN GENERAL THEY'RE SDH DEFICIENT, MULTI-FOCAL MEANING THEY'RE OFTEN IN SEVERAL PLACES AT ONCE. THEY TEND TO BE IN THE STOMACH. AND THEY DON'T HAVE MUTATIONS IN KINASE GENES. AND I ALREADY LEARNED THAT THIS IS OUT OF DATE IT SHOULD SAY THERE ARE THREE OPEN STUDIES. SO WE WENT FROM HAVING NO STUDIES FOR THESE WILDTYPE OR SDH DEFICIENT OR PEDIATRIC GIST TO HAVING THREE STUDIES. THIS IS THROUGH WORK THAT SHE AND KATIE AND OTHERS EARLY ON IDENTIFIED THAT A RECEPTOR CALLED INS LINE LIGHT GROWTH FACTOR RECEPTOR ONE WAS HIGHLY EXPRESSED IN THESE TYPES OF TUMORS AND DISTINCTION TO THE MUTANT THAT ARE MORE SUSCEPTIBLE TO GLEEVEC. THAT STUDY WAS GOING THROUGH IRB. [NOT AUDIBLE] SO THAT'S REALLY GREAT. THAT WILL BE OPEN AT MULTIPLE INSTITUTIONS AROUND THE COUNTRY. THEN A STUDY THAT'S SOON TO OPEN, I WOULD GUESS MORE LIKE TWO OR THREE MONTHS IS DRUG CALLED VANDETINIV THAT IS BASED ON SOME INFORMATION WE'VE LEARNED ABOUT THE EPI GENETIC ALTERATIONS AND SOME RELATED TUMORS THAT HAVE SIMILAR MUTATIONS IN DEHYDROGENASE. WE'VE SEEN SOME RESPONSES IN KIDNEY CANCER WITH THESE MU TIKES A DRUG CALLED VANDETANIB THAT INHIBITS VASCULAR GROWTH FACTOR RECEPTORS. IT INHIBITS WE THINK THE ABILITY OF THE TUMOR TO GET OXYGEN THROUGH BLOOD VESSELS. SO IT'S NEVER BEEN TRIED IN GIST. WE'VE USED IT IN OTHER PEDIATRIC TUMORS, OTHER ENDOCRINE TUMORS THIS IS THE STUDY THAT WILL OPEN INITIALLY JUST HERE BECAUSE WE HAD TROUBLE GETTING THE DRUG AND ALL THESE OTHER ISSUES, OBVIOUSLY IF IT SHOWS PROMISE WE'LL TRY TO GET IT OPEN AS MANY PLACES AS POSSIBLE. I 'POM GUYS FOR LEAVING OUT, KATIE REMINDED ME THERE IS ALSO A STUDY OPENING FOR PEDIATRIC GIST SPECIFICALLY WITH -- YOU WANT TO SAY A WORD OR TWO? -- [NOT AUDIBLE] >> THERE IS A LITTLE BIT OF EXPERIENCE THERE. IS ONE THAT WE USE IN ADULT GIST AS WELL. WE HAVE NOT USED EITHER OF THESE DRUGS IN GIST AND SO WE HAVE NO REASON TO BELIEVE ONE IS MORE LIKELY TO WORK THAN ANOTHER. IF WE DID WE WOULD PUT THEM IN SOME KIND OF PRIORITY. AND THERE'S NO REASON IF YOU DECIDE TO GO ON ONE AND THAT YOU DO WELL THEN PROGRESS THAT YOU COULDN'T THEN SWITCH OVER TO THE OTHER. JUST BECAUSE YOU START ON ONE DOESN'T MEAN YOU'RE LIMITING YOUR OPTIONS. SOME OF THIS WILL BE A PERSONAL CHOICE DEPENDING ON WHAT IS ENTAILED. YOU WOULD HAVE ALL OF THOSE OPTIONS OPEN IN ANY SEQUENCE. I WANT TO MAKE THAT CLEAR. THEN I ALSO WANT TO TALK A LITTLE BIT ABOUT FUTURE CLINICS WHICH, FOR THOSE OF YOU THAT ARE HERE FOR THE FIRST TIME, MAY NOT MEAN MUCH BUT NOR OUR ADVOCATE FRIENDS WE'VE HAD A TRANSITION BECAUSE WHEN I STARTED THIS CLINIC I GOT POST DOC WHO IS KNOWN TO MANY OF YOU WHO REALLY TURNED THIS IN TO A FULL-TIME JOB. HE WAS FANTASTIC. MATE THIS CLINIC WORK AND HE LEFT ABOUT SIX MONTHS AGO OR SO, I'M LOSING TRACK OF TIME, AWHILE AGO. WHEN DID HE LEAVE? HE WENT TO INDUSTRY THERE IS A LOT OF CONCERN ABOUT COOKS WE, NO WE'LL KEEP HAVING THE CLINICS. LITTLE DID I KNOW THAT HOW MUCH TIME IT TOOK. BELIEVE ME IT'S A LOT OF WORK AND I HAD A LOT OF HELP. BUT WE ARE PROBABLY BECAUSE NOW FOR THE FIRST TIME WE ACTUALLY DO HAVE TREATMENTS AND WE'LL PROBABLY CHANGE FROM EVERY SIX MONTHS TO HAVING THE CLINIC ONCE A YEAR. BECAUSE WE HOPE MANY OF YOU WILL BE ON STUDIES NOW AND WE'LL SEE YOU AT OUR VARIOUS INSTITUTIONS AND SO THERE WILL BE LOTS OF OPTIONS FOR YOU WHERE AS BEFORE WE HAD NO TREATMENT WE JUST SAW YOU WHEN WE HAD OUR CLINICS EVERY SIX MONTHS. THAT'S ONE CHANGE THAT WE'RE LOOKING FORWARD TO. BUT WE PLAN TO CONTINUE TO SEE EVERYONE IF THEY WANT TO COME ONCE A YEAR. IT'S GOOD FOR ALL OF US DOCS TO GET TOGETHER PERIODICALLY, AS WELL. SO, WHAT WE'VE LEARNED ABOUT THE GENETICS OF THIS IS THE OVERWHELMING MAJORITY OF THESE, WHAT WE NOW HAVE MORE CAREFULLY DEFINED AS SDH DEFICIENT GIST, OR MULTI-FOCAL GASTRIC TUMORS. THEY LACK SDH IMMUNOREACTIVITY. AND OF THOSE HA HAVE THESE CHARACTERISTICS OVER 90% AS I MENTIONED OVER EXPRESSED INSULIN GROWTH FACTOR ONE RECEPTOR. SO INTERESTINGLY SOMETHING WE DIDN'T KNOW THAT BECOMING MORE APPARENT IS MOST OF THE TUMORS THAT ARE SDH MUTANT THE SDH MU NATION IS IN THE GERMLINE. THAT IS NOT JUST IN THE TUMOR BUT IT'S IN EVERY CELL. WE'RE STILL NOT SURE WHETHER IT'S 07% OR 90% BUT IT'S HIGH. MANY OF THE PATIENTS THAT WE FIND THESE IN ACTUALLY HAVE THAT MUTATION IN THE GERMLINE. WHAT THAT MEANS IS THAT IT IS IN EVERY CELL. AND SO EVERY CELL HAS ONE NORMAL COPY AND ONE MUTANT. WHAT HAPPENS IN THE TUMORS YOU LOSE THAT NORMAL COPY SOMEHOW THAT LEADS TO THE DEVELOPMENT OF THE TUMOR. BUT IT ALSO HAS RAMIFICATIONS FOR GENETIC COUNSELING AND ALL KINDS OF ISSUES THAT WE'RE STILL WORKING ON, WHAT IS THE BEST WAY TO HANDLE THIS BECAUSE IT WOULD AFFECT HOW YOU SCREEN. HOW YOU WOULD LOOK FOR OTHER DISEASES IN THE FUTURE AND UNTIL WE HAVE EFFECTIVE SCREENING WE'RE NOT SURE WHAT TO DO WITH THIS INFORMATION. AND WHAT WE'RE AT THE POINT NOW I THINK IS WHEN WE HAVE THAT INFORMATION IN A CAREFULLY CERTIFIED TEST WHERE WE KNOW THE ACCURACY OF THE TEST WE LEAVE IT UP TO OUR PATIENTS TO SAY, DO YOU WANT TO KNOW THIS INFORMATION. THERE ARE LA QUILT MAT PRESENCE TO SAY YES OR KNOW WE'RE ALL TRYING TO LEARN HOW TO BEST HANDLE THIS INFORMATION. INFORMATION TOGETHER. ONE OF THE OTHER INTERESTING THINGS ABOUT THESE PARTICULAR TUMORS IS THAT THEY ARE WHAT WE CALL QUIET GENETICALLY. THAT IS MANY CANCERS, MANY TUMORS HAVE CHROMOSOMES THAT GET ALTERED. MANY DIFFERENT ALTERATIONS. AND THAT'S THE CASE IN THE KIT MUTANT GIST AND ADULT GIST IF YOU LOOK AT THE CHROMOSOMES THERE ARE A NUMBER OF ALTERATIONS WHICH IS WHAT WE SEE IN ALMOST EVERY CANCER. IN THESE KINDS OF TUMORS THEY REALLY LOOK PRETTY NORMAL AND WE THINK ONE OF THE REASONS YOU DON'T SEE MANY CHROMOSOMAL CHANGES IS THAT IT CORRELATES VERY STRONGLY WITH A CHANGE IN WHAT WE CALL EPIGENETIC. THAT IS NOT THAT THE GENE ITSELF IS CHANGED BUT THE WAY THE GENE IS PACKAGED, WHAT WE CALL METHYLATION OF THE WAY THE CHROMOSOMES ARE PUT TOGETHER GETS ALTERED IN A WAY HA WE DON'T FULLY UNDERSTAND BUT IT AFFECTS WHICH GENES ARE EXPRESSED. IT'S CALLED METHYLATION. IT IS IT IS NOT A GENETIC CHANGE IT'S NOT IN HAIRED BUT SEEMS TO CHANGE THE WAY THE CHROMOSOMES LOOK TO THE BODY. PROBABLY THE BEST WAY I CAN DESCRIBE IT. AND SO THIS IS SORT OF THE DATA ON THE FIRST 90 PATIENTS. I JUST WANT TO GIVE YOU A SENSE OF, HERE IS -- THESE ARE NOT DONE UNDER STRINGENT CONDITIONS, THESE ARE RESEARCH, WE FIND THESE BY RESEARCH SO IF WE FIND THIS WE WOULD THEN, IF YOU WANTED TO GET THAT INFORMATION WE WOULD THEN HAVE TO DO IT UNDER A MORE RIGID TEST TO CONFIRM IT AND THAT'S WHEN THEN WE'D MAKE THAT INFORMATION AVAILABLE IF YOU WANTED TO KNOW. BUT YOU CAN SEE HOW MANY OF THESE TUMORS ALREADY WE FOUND THESE MUTATIONS IN THESE GENES CALLED SDH. AND ALL OF THESE Ds HERE ARE THE CHANGES I WAS TALKING ABOUT THAT IS THE METHYLATION CHANGES OR THE EPIGENETIC CHANGES. SO IT'S PRETTY COMMON. WE STILL HAVE A NUMBER OF THESE THAT WE HAVEN'T LOOKED AT. BUT THIS IS INFORMATION THAT WE HAD NO IDEA ABOUT FOUR YEARS AGO. THIS IS JUST THE SLIDE THAT SHOWS -- THIS IS WHAT A NORMAL ADULT GIST LOOKS LIKE. THIS IS DEHYDROGENASE. THIS IS THE TUMOR IN WHAT WE CALL AN SDH DEFICIENT GIST YOU CAN SEE THEY LOOK PRETTY MUCH THE SAME UNDER THE MICROSCOPE BUT IF YOU STAIN THESE TUMOR CELLS DON'T EXPRESS THIS PROTEIN AND THIS DOESN'T SHOW VERY WELL BECAUSE OF THE LIGHT, BUT THE ONES THAT HAVE THIS DEHYDROGENASE MISSING ALL OF THIS RED, THAT SHOWS THAT THE GENOME IS HYPERMETHYLATED. SO THESE TUMORS LOOK MUCH DIFFERENT THAN THE NORMAL MUTANT, KIT MUTANT GISTS WHICH ARE THESE TUMORS. SO WE CAN REALLY TELL, VERY DISTINCT PATTERN, EVEN THOUGH UNDER THE MICROSCOPE THEY REALLY LOOK PRETTY SIMILAR. SO, WE'RE TRYING TO USE THAT INFORMATION TO DEVELOP THERAPIES AND SO AS YOU HEARD WE KNOW ABOUT THE IGF1 OVER EXPRESSION THAT'S ONE THERAPY. WE KNOW ABOUT ONE OF THE THINGS THAT DEHYDROGENASE DEFICIENCY DOES IS IT POISONS ANOTHER -- BESIDES CAUSING HYPERMETHYLATION IT CHANGES ANOTHER ENZYME WHICH WE THINK HAS TO DO WITH BLOOD VESSEL GROWTH THAT'S ONE OF THE REASONS WE HOPE THIS THE DRUG MAY BE ANOTHER APPROACH. YOU CAN SEE THE COLORS BETTER IN THE BACK. THIS IS JUST JUST -- MAYBE TOO MUCH INFORMATION, BUT THIS IS WHAT DNA LOOKS LIKE. THIS IS THE DOUBLE HELIX THAT YOU ALL HAVE HEARD ABOUT. AND WHAT WE SEE HERE IS ONE OF THE BASIS, CALLED CYTOSEEN. NORMALLY THERE IS THIS METHAL CYTOSINE THAT AFFECTS OUT TIGHTLY THE DNA IS ACCESSIBLE. WHAT WE THINK HAPPENED IS THAT THERE IS THIS ENZYME CALLED TET 2 IT THEN TAKES THAT METHYL CYTOSINE AND IT ADDS HYDROXY GROUP. IT THEN ALLOWS DNA TO GET UNMETHYLATED. AND WE THINK THAT HAVING ALL THIS -- WE THINK THAT HAVING ALL THAT EXTRA DOESN'T LET THAT ENZYME WORK MAYBE THAT'S WHY THE DNA GETS SO MUCH OVER METHYLATION. I HAVE JUST WRITTEN HERE THIS TET ENZYME CAUSES HYDROXY METHYLATION THEN THAT ALLOWS THE GENOME -- THE DNA TO BE ACCESSIBLE TO MAKE PROTEIN. WHEN IT'S IN THIS FORM YOU CAN'T MAKE CERTAIN PROTEINS EVEN THOUGH THERE'S NO MUTATION IT WON'T MAKE, BECAUSE REMEMBER DNA USUALLY ITS JOB TO ENCODE, TO TELL BODY TO MAKE CERTAIN PROTEINS. SO WHEN IT GETS STUCK IN THIS STATE BY POISONING THIS ENZYME, THERE'S A WHOLE BUNCH OF NORMAL PROTEINS THAT DON'T GET MADE. THAT'S ANOTHER THING WE'RE LOOKING FOR THAT THERE ARE ONE OR TWO THAT ARE CRITICAL THAT WE CAN THEN TRY TO BLOCK BUT WE DON'T HAVE THAT INFORMATION YET. JUST A QUICK WORD ON TREATMENT APPROACHES. MOST OF THESE TUMORS HAVE WHAT WE CALL INDOLENT GROWTH THAT'S A GOOD THING, IT MEANS THEY GROW VERY SLOWLY, EVEN THOUGH WE DON'T HAVE GOOD TREATMENTS FOR THEM. AND THAT REALLY MEANS THAT WE'RE VERY RELIANT ON OUR SURGICAL COLLEAGUES TO RESECT THEM. AND EVEN WHEN IT GETS RESECTED IF IT COMES BACK, SOME TIMES WE RESECT IT AGAIN AND PATIENTS CAN GO YEARS AND YEARS. SO IT DOESN'T GROW RAPIDLY. WHAT WE HAVE LEARNED BECAUSE THEY'RE MULTI-FOCAL AND BECAUSE PATIENTS WILL OFTEN PRESENT WITH PAIN OR BLEEDING, RATHER THAN TRYING TO TAKE OUT EVERY TUMOR BECAUSE SOMETIMES TO DO THAT YOU MAY HAVE TO TAKE OUT SO MUCH OF THE STOMACH THAT YOU ACTUALLY CREATE MORE SYMPTOMS THAN WHAT YOU WOULD HAVE BY THE DISEASE ITSELF. AND SO WHAT WE'VE LEARN ASKED WE TRY TO -- OUR SURGEONS THAT KNOW HOW TO TREAT THIS DISEASE TRY TO TREAT THE SYMPTOMS, THE PAIN OR OBSTRUCTION OR BLEEDING AND NOT TRY TO TAKE OUT EVERY LAST PART OF THE TUMOR BECAUSE WE KNOW PATIENTS CAN LIVE FOR YEARS AND YEARS WITH A SLOW GROWING TUMOR. AND SO THAT'S ONE OF THE THINGS WE'VE LEARNED. ACTUALLY, KATIE, I GUESS WE CAN DEBATE THIS. I RARELY IF EVER SEE OBJECTIVE RESPONSES. WE WERE ACTUALLY DISCUSSING THIS. THERE IS A REPORT THAT SOME OF THESE, QUOTE, WILDTYPE GISTS RESPOND TO THESE KINASE INHIBITORS BUT THIS WAS WRITTEN AWHILE AGO AND I THINK WHAT WE'RE TALKING ABOUT ARE THE SDH MUTANT PEDIATRIC TYPE GIST DON'T -- HARDLY EVER DO YOU SEE THE TUMOR SHRINK ON THESE KINASE INHIBITORS. WHAT WE HAVE SEEN MANY HAVE SEEN IS THAT THE TUMOR IS GROWING THEN YOU START THAT, IT SEEMS TO SOMETIMES MAKE THE TUMOR STOP GROWING WHICH IS AGAIN JUST TURNING IT IN TO AN INDOLENT PROCESS AGAIN AND THAT'S GOOD. BUT I GUESS THERE IS STILL SOME DEBATE ABOUT THIS I THINK PART OF THE THING WE'LL LEARN MAYBE WITH KATIE'S STUDY, WHAT IS THE PERCENTAGE OF ACTUAL TUMOR SHRINKAGE. SO MAYBE I SPOKE A LITTLE SOON HERE. THIS IS MY BIAS. AS I MENTIONED 90% EXPRESS HIGH LEVELS OF THIS GROWTH FACTOR RECEPTOR AND THAT'S WHY ONE AREA TO TRY IS THIS OSI WHICH INHIBITS THAT GROWTH FACTOR. THAT'S AS I MENTIONED THIS WILL BE A STUDY RUN BY DR. VAN MARIN THROUGH SARC. AND I BRIEFLY MENTIONED SDH DEFICIENCY LEADS TO SUCCINATE ACCUMULATION. WE THINK THAT MAY ALLOW THEM RESPOND TO VEGF INHIBITORS AND WE TALKED A LITTLE BIT ABOUT THAT. JUST TO END OUR FUTURE PLANS ARE ARE -- WE WILL CONTINUE TO HAVE THIS I GUESS FOR CONVENIENCE WE CALL IT WILDTYPE GIST CLINIC. BUT RATHER THAN HAVING IT TWICE A YEAR WE'RE GOING TO CHANGE IT TO A ONCE A YEAR WHERE WE BRING IN THE DOCS AND PEOPLE THAT WANT TO COME SPEND TIME AND MEET EVERYONE. AND ALSO AS YOU'LL FIND OUT WE HAVE REALLY GREAT SUPPORT, NUTRITIONISTS AND GENETIC COUNSELORS AND DIETITIANS AND PSYCHOLOGISTS AND ANY KIND OF SUPPORT THAT WE CAN PROVIDE. WE'RE REALLY -- WE'LL BE OPEN FULL TIME IN OUR CLINIC AND ALL THE OTHER DOCTORS THAT HAVE CLINICS THAT ATTEND THIS CLINIC IN BOSTON AND UTAH IN HOUSTON -- IN ST. JUDE IN MEMPHIS, I KEEP FORGETTING. PHILADELPHIA. ALL OVER THE COUNTRY. COMPOST TO COAST. AND SO WE'RE HOPE HALF THESE STUDIES WILL BE ACCESSIBLE TO ANYONE THAT HAS AN INTEREST IN TRYING A NEW THERAPY. AND AS I MENTIONED AT THE BEGINNING YOU CAN ENTER ON ONE STUDY AND THEN ANOTHER. IF THE FIRST STUDY DOESN'T SEEM TO BE DOING THE TRICK. HOPEFULLY WE'LL ALL LEARN TOGETHER AND WE WERE NOT GOING TO STOP THERE. AS WE LEARN MOREF WE IDENTIFY SOME OF THE OTHER GENES THAT DON'T GET EXPRESSED MAYBE WE CAN THEN HAVE OTHER THERAPIES AS WELL. THIS IS THE BEGINNING. I THINK THAT IS IT. I'M HAPPY TO TAKE ANY QUESTIONS. AND I'M LOOKING FORWARD TO MEETING EACH OF YOU TOMORROW. [ NOT AUDIBLE ] AGE LIMIT FOR THE STUDY. [ NOT AUDIBLE ] MY HOPE IS -- MY HOPE IS THAT WE JUST LIMIT IT TO SDH DEFICIENCY. BECAUSE TO ME THE AGE IS IRRELEVANT. [ NOT AUDIBLE ] WELL, ACTUALLY, YOU CAN TALK ABOUT THE OSI. [ NOT AUDIBLE ] MY SENSE IS, AGAIN, ONE OF THE THINGS WE'VE LEARNED I DIDN'T PUT IT IN HERE, A DOCTOR WHO IS PATHOLOGIST HAS BEEN STUDYING GISTS FOR MANY YEARS HAS SHOWN ME DATE THAT THAT THE IGF1 RECEPTOR OVER EXPRESSION IS2xe ALMOST IF NOT 100% EXCLUSIVELY THOSE GASTRIC GISTS. SO I THINK WE'RE TALKING ABOUT BASICALLY WILDTYPE NONMUTANT GASTRIC GIST, IS THAT WILL MAKE UP VAST MAJORITY OF PATIENTS WOULD GO ON THAT PARTICULAR STUDY. WHICH WOULD BASICALLY BE SIMILAR TO WHAT THE VANTENIN STUDY IS. I DON'T KNOW THAT WE'VE SEEN SDH DEFICIENT TUMORS NOT IN THE STOMACH. MAYBE ONE, BUT I CAN'T REMEMBER ANY OFF THE TOP OF MY HEAD. [ NOT AUDIBLE ] >> THAT'S A REALLY GOOD QUESTION. SO, AS I SAID, THERE ARE PROBABLY A FEW CASES WHERE WE DON'T -- WHERE THERE SEEMS TO BE SDH DEFICIENCY MAY BE WHAT WE CALL AN ACQUIRED MUTATION ONLY IN THE TUMOR. AND NOT IN EVERY CELL IN YOUR BODY. THAT'S THE DIFFERENCE. TECHNICAL TERM IS A SOMATIC MU NATION AS OPPOSED TO A GERM-LINE MUTATION. SO -- [ NOT AUDIBLE ] YES. ONE TEST IS IN THE TUMOR ITSELF THE OTHER TEST IS JUST IN BLOOD. AND WE'LL TALK ABOUT THAT. AGAIN, WE WOULDN'T DO ANY -- THIS IS ONLY DONE IF YOU'RE INTERESTED IF IT'S REALLY -- [ NOT AUDIBLE ] IT'S A VERY GOOD QUESTION. I'M SURE ALL OF YOU HAVE HEARD SOME OF THE CONTROVERSY IN THE NEWSPAPERS OVER THE LAST YEAR ON MAMMOGRAPHY SCREENING FOR BREAST CANCER AND CERTAINLY PSA SCREENING FOR PROSTATE CANCER. SO -- THE REASON IT BECAME CONTROVERSIAL IS WHY WOULD YOU SCREEN FOR SOMETHING THAT YOU CAN'T DO ANYTHING ABOUT. IF I GOT SCREENED FOR SOMETHING AND THEY SAID WELL, TOO BAD, SOME PEOPLE WOULD WANT TO KNOW ANYWAY AND SOME WOULD SAY, I DON'T WANT TO LIVE WITH THAT, I WOULD JUST RATHER NOT KNOW AND NOT WORRY ABOUT IT. SO SOME PEOPLE ARE -- SOME OF IT IS JUST -- THE MOST IMPORTANT TIME TO KNOW SEEMS TO ME, THIS IS MY OPINION, IS IF I COULD CHANGE SOMETHING WITH THAT KNOWLEDGE, IF I HAD KNOWLEDGE THAT I CAN'T ACT ON IT WOULD BECOME SOMEWHAT PERSONAL CHOICE M. PEOPLE THINK THAT MORE KNOWLEDGE YOU HAVE THE BETTER. SOME PEOPLE FEEL LIKE SOMETIMES YOU KNOW TOO MUCH ESPECIALLY IF YOU CAN'T DO ANYTHING ABOUT IT. [ NOT AUDIBLE ] THAT'S AN OPTION. THAT IS SOMETHING THAT WE OFTEN TALK ABOUT. AGAIN IT WOULD DEPEND -- IF YOU HAD A CHILD YOUR CHILD HAD A GERM-LINE MUTATION WOULD YOU WANT TO KNOW, DID IT COME FROM MY MOTHER, MY FATHER. MAYBE THAT'S IMPORTANT TO KNOW, MAYBE IT'S NOT. IT'S A DISCUSSION THAT WE ACTUALLY -- WHAT WE ENCOURAGE THAT YOU HAVE THE DISCUSSION WITH OUR GENETIC COUNSELORS THEY'RE THE ONES TRAINED AND EQUIPPED FOG OVERALL THOSE ISSUES. COURSE WE'RE HAPPY TO TALK TO YOU AS WELL BUT THAT'S THEIR SPECIFIC PROFESSIONAL. BUT I THINK THE ISSUE PRIMARILY IS ONE OF, IS THERE INFORMATION THAT YOU CAN ACTUALLY -- THAT YOU CAN DO SOMETHING, THAT YOU CAN ACT UPON OR IS IT JUST SOMETHING THAT YOU'RE GOING TO KNOW AND NOT HAVE ANY ACTIONABLE -- PEOPLE HAVE DIFFERENT OPINIONS ABOUT THAT. [ NOT AUDIBLE ] OKAY.—m I HOPE YOU GUYS HAVE A VERY NICE EVENING AND WE LOOK FORWARD TO MEETING ALL OF YOU TOMORROW. ANYBODY ELSE HAVE ANY -- [ NOT AUDIBLE ] I WANT TO LET THEM OUT TO GET SOMETHING BEFORE -- APPARENTLY LEAVE AT 6:30, RIGHT? [APPLAUSE]