I'D LIKE TO WELCOME EVERYBODY TO OUR TUMOR BOARD, PARTICULARLY WELCOME OUR COLLEAGUES WHO ARE JOINING US FOR THE EPENDYMOMA CONSENSUS CONFERENCE. WELCOME TO THE NIH, AND WELCOME TO THE HIGH LEVEL OF SECURITY RIVALED ONLY BY FORT KNOX. SO I'M GLAD MOST OF OF YOU MADE IT. THERE WAS A LITTLE BIT OF AN ISSUE AT GATEWAY CENTER, SO KEN IS GOING TO BE A BIT LATE, BUT HE DID TEXT ME AND TOLD ME WE SHOULD CARRY ON. SO, WE WILL DO SO. HOPEFULLY HE WILL BE HERE SOON. ADDITIONALLY, THE PANELISTS SET UP SO THAT AS THE PRESENTATIONS ARE GOING WE HAVE WHAT THEY CALL A CHEAT SCREEN, BUT THAT CHEAT SCREEN IS NOT FUNCTIONING. SO THE PANEL WILL BE LOOKING THIS WAY UNTIL THEY REPLACE THAT. SO WE WILL MAKE DO. SO WE HAVE THREE CASES THIS MORNING. TWO ADULT CASES THAT WE THINK ARE COMPLEMENTARY, BOTH OF PATIENTS WITH SPINAL CORD EPENDYMOMA. AGAIN, TO GIVE SORT OF A SPECTRUM OF THAT DISEASE, AND HOW LIMITED OUR KNOWLEDGE IS ABOUT PREDICTION OF RISK AND DISEASE BIOLOGY, AND THEN WE HAVE A PEDIATRIC CASE TO FOLLOW. SO I THINK WE WILL GET STARTED WITH THE FIRST ADULT CASE. >> GOOD MORNING. I'M ONE OF THE CLINICAL FELLOWS HERE AT THE NIH. STARTING WITH THE FIRST CASE, THIS IS A 50 YEARS OLD, RIGHT-HANDED MAN, HEALTHILY BUT PROGRESSIVE LOSS OF SENSATION, LOWER EXTREMITIES, IMAGING WHICH WE'RE GOING TO SEE IN A LITTLE BIT SHOWED INTERMEDULLARY LESION AND EDEMA, WE HAVE SCREENED HIS NEUROAXIS, NEGATIVE FOR OTHER LESIONS. >> DR. HEIST, DO YOU WANT TO DESCRIBE THE IMAGING FINDINGS? >> YEAH, THIS IS A MAN, HE WAS DEFINITELY AFRAID OF SURGERY. HE TALKED TO OTHER NEUROSURGEONS AROUND THE COUNTRY AND WAS CONVINCED HE WOULD BE PARALYZED IF HE HAD SURGERY. THIS IS T1 SCAN WITH CONTRAST, SHOWS AN ENHANCING LESION, INTERMEDULLARY LESION, SUPERIOR AND INFERIOR, IT'S THE C5-6 LEVEL. >> OKAY. >> QUICKLY, JOHN, WHAT WOULD YOU PUT IN THE DIFFERENTIAL? >> WELL, CENTRAL INTERMEDULLARY LESION, APPEARED TO BE AN EPENDYMOMA. IT'S LESS LIKELY THE ASTROCYTOMA, THOSE ARE THE MAIN. OBVIOUSLY ANY CELL OF ORIGIN IN THE SPINAL CORD CAN GIVE RISE TO A TUMOR BUT THOSE ARE THE MOST LIKELY OBVIOUSLY. GIVEN WE'RE TALKING AT AN EPENDYMOMA CONFERENCE IT'S MOST LIKELY EPENDYMOMA. >> OKAY. NEXT? >> OKAY. SO PATIENT WENT UNDER SURGERY WITH LAMINECTOMY WITH TUMOR RESECTION HERE AT NIH, BEAUTIFUL RESECTION WITH CAPSULE DISSECTED WITH TUMOR WAS REMOVED WITHOUT CAPSULE DISRUPTION. THIS IS WE'RE SHOWING HERE PRE AND POST SURGERY. >> RIGHT. YOU CAN SEE THERE'S NO ENHANCEMENT ON THE POST OP IMAGE. THAT'S PRETTY TYPICAL NOW DAYS WITH MICROSURGICAL TECHNIQUES. SO, THE DOCTOR DID A BEAUTIFUL JOB. WE USED NEURAL MONITORING TO REDUCE RISK OF COMPLICATION NEURAL DEFICIT, AND THE MAIN THING WITH THIS GUY WAS TO GET HIM TO GO FOR SURGERY BECAUSE EVERYBODY TOLD HIM THE LAUNDRY LIST OF WHAT COULD GO WRONG AND HE WAS CONVINCED HE WOULD BE PARALYZED IF HE HAD SURGERY. >> OKAY, NEXT? >> THIS IS PATHOLOGY. MARTHA? >> YES. >> TURN ON YOUR MICROPHONE. >> SO THIS IS A COUPLE OF H&E STAINED SECTIONS OF THE LESION. SO WE HAVE HERE A LOW TO HIGH POWER SECTION SHOWING DEFINITELY A CLASSICAL FEATURE OF A CLASSICAL EPENDYMOMA, THE SO-CALLED ROSETTE. SORRY, I DON'T HAVE AN ARROW. TRUST ME. SOMEONE IS SHOWING. WHO IS THIS? [LAUGHTER] OH, VERY WELL. OKAY. SO NUMEROUS VASCULAR ROSETTES, AN EPENDMYAL CANAL. VERY GOOD. NEXT SLIDE. MONO HISTOCHEMISTRY, THIS DAY AND AGE SO MANY MOLECULAR CAN PROVE US WRONG, YOU GO AHEAD AND CAN DO SOME IMMUNOHISTOCHEMISTRY, ACCENTUATION OF -- OKAY, CLASSICAL ACCENTUATION OF PERIVASCULAR SPACES, EMA SHOWING CLASSICAL DOT-LIKE FEATURE, APLASIA, CLASSICAL EXAMPLE OF EPENDYMOMA GRADE 2. >> THE EPENDYMOMA DISCUSSION, MANAGEMENT APPROACH AFTERWARD. >> SO I'LL ASK THE PANEL. SO, TOM? >> I THINK FOR THIS CASE OBSERVATION WOULD BE APPROPRIATE. WHAT WE LIKE TO HEAR FROM THE NEUROSURGEON IS THE TUMOR WAS RESECTED EN BLOC, THAT'S VERY HELPFUL TO US, THERE WERE NO ADVERSE FEATURES OR INTRAOPERATIVE FINDINGS THAT COULD LEAD TO INDICATION FOR THE RADIATION THERAPY. IF IT WAS QUESTIONABLE WE WOULDN'T BE EAGER TO TREAT THE POSTOPERATIVE IMAGING OFTEN IS DIFFICULT OR COULD BE DIFFICULT TO INTERPRET, AND I THINK THAT ALLOWING MORE TIME TO PASS AND TO HAVE NICE SOLID IMAGING POSTOPERATIVELY IS ALSO HELPFUL IN EVALUATING THESE PATIENTS. >> GREAT. ANY COMMENTS, THOUGHTS, FOR THE AUDIENCE? WE HAVE A MICROPHONE, SO WE ARE BEING BROADCAST, SO IT IS IMPORTANT THAT EVERYBODY IS ON A MICROPHONE. >> WHAT'S YOUR FEELING ABOUT LP FOR CYTOLOGY TO COMPLETE STAGING? >> (INAUDIBLE). >> SO, AGAIN, THE PANEL, WE DO NEED TO BE ON THE -- I THINK OUR EXPERIENCE WITH LUMBAR PUNCTURE, CSS CYTOLOGY SUGGESTS IT'S NOT A VERY GOOD EXAM, AND WE PUBLISHED YEARS AGO AN ARTICLE WHERE PATIENTS WHO HAD CLEAR EVIDENCE OF METASTATIC DISEASE BY MRI HAD NEGATIVE CYTOLOGY, SO THERE'S -- THAT TEST PROBABLY IS NOT A GOOD ONE. >> AND I WOULD CONCUR, VERY DIFFICULT TO FIND THE TUMOR CELLS, EVEN WHEN YOU KNOW THEY ARE THERE. TERRIFIC. SO LET'S MOVE TO THE NEXT CASE. I'M GOING TO ASK DR. CHRISTINE CORDOVA TO COME PRESENT THIS PATIENT. >> GOOD MORNING. SO SECOND ADULT CASE, SO THIS PATIENT INITIALLY PRESENTED IN 2012, 28-YEAR-OLD LAW STUDENT WITH NO PRIOR MEDICAL HISTORY. PRESENTED WITH NEW NECK PAIN, EXTENDING DOWN INTO THE ANTERIOR STERNAL AREA AND LOWER BACK PAIN. THIS WAS TREATED INITIALLY WITH MASSAGE, HE VISITED A CHIROPRACTOR, DID ACUPUNCTURE, NOTHING WORKED. AND EVENTUALLY WAS GIVEN MEDROL DOSEPAK. HE WAS UNABLE TO MOVE HIS NECK A FEW DAYS IN AND PRESENTED TO AN E.R. WE HAVE THE FOLLOWING IMAGING. SO HERE ON SEQUENCES WE CAN SEE THERE ARE SEVERAL NODULES THROUGHOUT THE SPINE, LARGEST OF WHICH IS ABOUT C1 TO C4. AND HERE'S A DIFFERENT SLICE. SO WE SEE THE CONTRAST IMAGES WITH SOME CYSTIC CHANGES ANTERIORLY AS WELL AS TUMOR WRAPPING AROUND MORE AT THE C4 LEVEL. >> OKAY. DR. HEIST, NOT TO PUT YOU ON THE SPOT, BUT WHAT ARE YOU THINKING? >> YOUR MICROPHONE. >> I THOUGHT I SAW ANOTHER LESION IN THE THECAL AREA, BUT ANYWAYS, YOU HAVE A LESION HERE AT C2-3, IT'S WRAPPING AROUND THE SPINAL CORD. IT COULD EITHER BE INTRADURAL OR IT COULD BE FROM THE SUBARACHNOID IS SPACE, LEPTOMENINGEAL SPREAD, FROM ELSEWHERE IN THE SPINE OR PRIMARY, BUT IT'S EXTRAMEDULLARY TUMOR, DOESN'T LOOK LIKE MENINGEOMA OR NEUROFIBROMA, MOST LIKELY A CSF METASTASIS FROM ANOTHER -- EITHER ANOTHER SITE OR -- YES. >> DR. PACKER? >> EVEN THOUGH THIS PATIENT'S A LITTLE OUTSIDE YOUR AGE RANGE, IF YOU WERE SENT THESE IMAGES, YOUR THOUGHTS AND RECOMMENDATIONS? >> WELL, I REALLY WOULD LIKE TO LOOK AT ALSO THE CORTEX. I WANT TO SEE IF THIS IS IN ONE SPACE, OR IS DISSEMINATED, DIFFERENTIAL IS WIDE, CLEARLY YOU'RE EVEN THINKING ABOUT THINGS AS UNUSUAL AS MIX OF PAPILLARY EPENDYMOMA THAT COULD BE IN MULTIPLE SPACES. THIS IS AN EPENDYMOMA CONFERENCE. SO THE LIKELIHOOD IS EPENDYMOMA IS SOMEWHERE IN THE DIFFERENTIAL DIAGNOSIS. BUT I DON'T THINK YOU KNOW AND YOU NEED TO GET A PIECE OF THIS, I ALSO THINK YOU NEED TO JUST BEFORE YOU START DECIDING HOW AGGRESSIVE YOU'RE GOING TO BE TO SEE HOW WIDELY DISSEMINATED THIS DISEASE IS. >> DO WE HAVE OTHER -- YEP, THERE WE GO. >> JUST TO NOTE, THE MRI BRAIN WAS NEGATIVE. >> WE DO SEE EVIDENCE ON THE -- IN THE THORACIC OF NODULAR DISEASE. >> (INAUDIBLE) IS THERE A RADIOLOGY IN THE AUDIENCE? >> YEAH, WE DO. >> IS THIS ON? WHAT ABOUT LOOKING AT THE BRAIN? >> WE DID. >> IT WAS NEGATIVE. >> IT WAS NEGATIVE. >> SO EVERYTHING THAT'S BEEN SAID MAKES PERFECT SENSE, BUT IT DOES LOOK LOOKIC IT'S EXTRAMEDULLARY, YOU HAVE TO HAVE A BROADER DIFFERENTIAL DIAGNOSIS, WE DON'T HAVE CROSS-SECTIONAL IMAGES, THAT'S ANOTHER THING THAT WOULD HELP IN DIFFERENTIAL. SOMETIMES THAT'S LOOK EXTRAMEDULLARY, BUT THAT IMAGE LOOKS LIKE IT'S COMPLETELY OUTSIDE. >> DIFFERENTIAL DIAGNOSIS? >> FROM A RADIOGRAPHIC -- >> CLASSIC, NEUROFIBROMA, DERMOID, DROP METS, PARAGANGLIOMA. HOW LONG DO YOU WANT THE LIST? >> WE HAVE 40 MINUTES. >> NEUROCYTOMA. >> GREAT. THANK YOU. SO DR. TAYLOR FROM NEUROSURGICAL STANDPOINT WHAT WOULD YOUR APPROACH BE, ALREADY DISSEMINATED BUT DO YOU HAVE THIS PRETTY PROMINENT HIGH C-SPINE LESION. >> I'M GLAD YOU SHOWED THE BRAIN BECAUSE AT FIRST I WAS UPSET. LIKE IF A RESIDENT SHOWED ME THIS AND THEY HADN'T SHOWN ME THE BRAIN I WOULD TOSS THEM OUT OF THE ROOM, THE FIRST THING I WANT TO SEE THE BRAIN. HAVING SAID THAT, OBVIOUSLY THERE'S A DIFFERENTIAL DIAGNOSIS HERE. AND WHAT'S THE PATIENT'S EXAM? >> WELL, WE DIDN'T SEE HIM BACK THEN. IT WAS EVIDENTLY JUST STIFF NECK. >> BECAUSE TO ME IT WOULD MAKE A BIG DIFFERENCE WHETHER OR NOT THIS IS A YOUNG OR OLD INDIVIDUAL, COMORBIDITIES. >> SO OTHERWISE HEALTHY. >> IF THIS WAS A 76-YEAR-OLD WHO HAD, YOU KNOW, CONGESTIVE HEART FAILURE I WOULD SEND THEM OFF TO FLORIDA, IF IT WAS A YOUNG INDIVIDUAL I WOULD BIOPSY THEM. TO BE HONEST WITH YOU, I PROBABLY WOULD NOT BIOPSY THE CERVICAL LESION, I WOULD BIOPSY THE THORACIC. I HAVEN'T SEEN THE FILMS NICELY IN MULTIPLE PLANES BUT THE KEY ISSUE HERE IS MAKING A TISSUE DIAGNOSIS AT FIRST. AND TACKLING THAT CERVICAL LESION COULD HAVE A RELATIVELY HIGH MORBIDITY AND IN THE FACE OF A METASTATIC LESION I'M NOT SURE IT WOULD BE WORTHWHILE IN AN SAY SYMPTOMATIC PATIENT. >> HE DOES HAVE A STIFF NECK, FROM HISTORY. >> YEAH, SO DO I. >> OKAY. >> HE'S A LAW STUDENT. >> A LAW STUDENT, WE SHOULD EUTHANIZE HIM. >> DR. HEIST, DO YOU AGREE WITH A BIOPSY OR WOULD YOU HAVE PROPOSED RESECTION? >> MICROPHONE PLEASE. >> WELL, A BIOPSY VERSUS A RESECTION, YOU GO IN, AND IF YOU CAN RESECT IT, YOU RESECT IT. IF YOU CAN BIOPSY IT AND YOU THINK YOU WOULD CAUSE NEURAL DEFICIT, THEN YOU STOP SHORT OF THAT. BUT YOU ALWAYS -- WHEN YOU HAVE A LESION -- NOW, WITH THAT LESION GOING ANTERIOR TO THE SPINAL CORD IT WOULD BE PRETTY UNLIKELY THAT YOU WOULD BE ABLE TO RESECT IT TOTALLY. SO I AGREE. WHAT YOUR GOAL IS TO MAKE A DIAGNOSIS, THAT'S THE PRIMARY GOAL. SO YOU COULD DO THE THORACIC OR THE CERVICAL ONE OR EVEN THE ONE, DROP MED AT L4 ON THE NERVE ROOT. >> THAT'S A BETTER CHOICE, L4, YOU'RE RIGHT. >> NEXT SLIDE. >> SO WHAT WAS DONE FIRST WAS CSF ANALYSIS, WHICH WAS NEGATIVE FOR MALIGNANT CELLS. PATIENT WENT TO HIS FIRST OF TWO SURGERIES, NOT PLANNED THAT WAY, BUT IN THE FIRST SURGERY ON OPENING THE DURA THEY COULD SEE THIS TUMOR AT C4, INVADING THE PIA, DISSECTED OFF, CAPSULE WAS ADHERENT TO THE CORD. THE TUMOR WAS ALSO INVADING THE CORD, DEBULKED. HOWEVER, ON THE IMAGE ON THE LEFT YOU CAN SEE THERE'S STILL SIGNIFICANT MASS, AT THAT LEVEL. SO THE DECISION WAS MADE TO RETURN TO THE O.R. FOR A SECOND PROCEDURE, AND ON THE RIGHT YOU CAN SEE THAT SECOND POST-OP FILM. >> CAN I ASK A QUESTION? WOULD EVERYONE HAVE DONE AN LP ON THIS PATIENT? I DON'T KNOW WHAT YOU'RE GOING TO BE GAINING OUT OF THE LP. YOU ALREADY KNEW THE DISEASE WAS DISSEMINATED. YOU WEREN'T GOING TO MAKE A TISSUE DIAGNOSIS BASED ON THE LP. IF THINGS WERE TIGHT YOU COULD SHIFT THAT SPINAL CORD AROUND A LITTLE BIT AND MAKE HIM SYMPTOMATIC. SO I DON'T UNDERSTAND THE RATIONALE FOR THE LP UNLESS SOMEONE WANTS TO ELUCIDATE. >> I WOULD YELL AT MY RESIDENTS IF THEY DID THAT. >> I MEAN, AS FAR AS -- SO THAT I HAVE DIFFICULTY WITH. THIS IS BEFORE WE EVER MET THE PATIENT. >> FIVE YEARS BEFORE WE DID. >> YEAH. MARK, A WANT A DO-OVER. THERE'S NECK PAIN, AND THERE'S NECK PAIN. IF YOU THINK IT'S NECK PAIN AND YOU'RE GOING TO DO ROUNDS THE NEXT DAY, THE GUY IS GOING TO BE QUADRIPLEGIC, YOU GET A FEEL, AND YOU KNOW YOU HAVE TO DECOMPRESS IT. THAT'S NOT SCIENCE. THAT'S SORT OF ART. SO I THINK THEY PROBABLY DID THE RIGHT THING HERE. >> RIGHT. AND I WOULD ACTUALLY -- I WAS GOING TO BRING THAT UP FOR DISCUSSION BECAUSE MOST LIKELY THIS IS A NEOPLASTIC PROCESS, MOST LIKELY WHATEVER THE DIAGNOSIS WAS THERE WOULD BE FOLLOWED BY RADIATION THERAPY AND I DON'T KNOW THAT EVEN IF HE DOESN'T HAVE LONG TRACK SIGNS HE HAS ANY WIGGLE ROOM IN CASE RADIATION CAUSES ANY EDEMA, AND THEN IT WOULD BE AN EMERGENCY ATTEMPT AT RESECTION WITH SOMEBODY GETTING PROGRESSIVE. >> IT'S A SCHWANN NO, SCHWANNOMA YOU'RE NOT GOING TO RADIATE HIM, THE MINUTE HE TURNS A HAIR YOU'RE GOING TO DO SONG. WE WOULDN'T RAID SOMEONE WHO HAS A SCHWANNOMA, MAYBE IT'S DIFFERENT IN CANADA BECAUSE WE DON'T MAKE AS MUCH MONEY. >> HE HAD NECK PAIN, NO NEUROLOGIC DEFICIT. >> OKAY. HE WAS DEBULKED. >> AND THE SECOND PROCEDURE THERE WERE ADDITIONAL TUMORS THAT WERE NOT VISIBLE ON MRI, AND MEDULLARY JUNCTION AND BRAINSTEM, BRAINSTEM ONES WERE LEFT IN PLACE. >> OKAY. >> WE HAVE FOUR PICTURES FROM PATHOLOGY. >> MARTHA? >> OKAY. SO I'M ACTUALLY VERY GLAD TO KNOW THE PATHOLOGIST, TO MAKE THE FINAL DIAGNOSIS. VERY IMPORTANT. SO, THESE ARE A COUPLE H&E STAINED SECTIONS, SIMILAR TO WHAT WE SAW BEFORE, THIS IS -- IT LOOKS LIKE A GLIAL LESION. YOU CAN SEE THERE ARE A LOT OF STRUCTURES THAT LOOK LIKE -- THE VASCULAR ROSETTES CERTAINLY TO THE LEFT, OH, ACTUALLY THIS AREA HERE, YEAH. YES. YEAH, OKAY. VASCULAR. >> RIGHT HERE. >> MAYBE A LITTLE BIT OF NECROSIS RIGHT THERE ON THE TOP, AND IN THE NEXT SLIDE ACTUALLY YOU NOTICE -- >> NEXT SLIDE. >> LET'S SEE. MAYBE A LITTLE BIT BETTER SO THE VASCULAR ROSETTES THERE BUT THERE ARE AREAS OF THE TUMOR DEPICTED RIGHT ON THE RIGHT SIDE OF THE SLIDE THAT THE CELLS ACTUALLY THEY GET ANGRIER LOOKING, THEY HAVE A HIGHER NC RATIO, THEY ARE MITOTIC ACTIVITIES. IF YOU GO TO THE PRIOR SLIDE, SORRY FOR THAT, THERE IS ACTUALLY AREAS THAT ARE GLOW MER LLOYD VASCULAR PROLIFERATION. YOU HAVE A GLIAL LESION WITH PSEUDOVASCULAR ROSEETTES, THE BASE DIAGNOSIS THIS IS EPENDYMOMA LESION, THERE AN EPENDYMOMA WITH APLASTIC FEATURES W.H.O. GRADE 3. >> CONSISTENT WITH WHAT THE OUTSIDE PATHOLOGY SAID IN 2012. NEXT SLIDE. >> AFTER SURGERY, IT WAS DISCUSSED, SOMEONE BROUGHT UP THE QUESTION OF CHEMOTHERAPY, IT WAS FELT CRANIOSPINAL RADIATION WAS THE BEST CHOICE. HE RECEIVED A TOTAL DOSE OF 50 GRAY OVER 20 FRACTIONS, 36 WAS IN 20 FRACTIONS FROM THE SPINE, SKULL BASE TO C4, T 4, T7, L3 WITH MORE BULKY TISSUE. >> TOM, WHAT DO YOU THINK ABOUT THIS PLAN? >> I THINK IT'S TOTALLY REASONABLE. THE ONLY QUESTION IN THIS CASE IS THE TOTAL DOSE. I THINK 50.4 IS SOMETHING THAT MOST PEOPLE WOULD BE COMFORTABLE WITH. ON OCCASION WOULD GO HIGHER TO 54 GRAY. THE THING TO BE CONCERNED ABOUT, THE PORTION OF THE CORD COMPRESSED, HOW DEVITALIZED IS THAT, HOW SENSITIVE WOULD THAT BE TO HIGH DOSE RADIATION, AND WE KNOW THERE'S PROBABLY INCREASED RISK OF CORD NECROSIS WHERE YOU HAD COMPRESSION, WE'VE SEEN THAT IN SOME PATIENTS BUT I THINK THIS IS A VERY GOOD PLAN. SO -- >> WOULD YOU CHANGE THE DOSING IF IT WAS DONE BY PROTON RATHER THAN PHOTON? >> NO, IT ALSO HAS TO DO WITH THE AMOUNT OF RESIDUAL TUMOR, SO IN THIS CASE RESECTING THE PRIMARY WHICH IS THE UPPER SPINAL CORD, AND I WOULD -- WE WOULD LIKE TO DO METASTASIZECTOMY ON REMAINING LESIONS, AGGRESSIVE FOR SOME PEOPLE BUT BASED ON FIRST PRINCIPLES LIKE TO HAVE THE LEAST AMOUNT OF RESIDUAL TUMOR PRESENT WHEN WE TREAT THESE PATIENTS, AND PEOPLE HAVE TO UNDERSTAND THAT RADIATION ESPECIALLY IN THIS CASE IS A ONE-TIME TREATMENT SO YOU CAN'T GO BACK AND FILL IN LATER. SO IT HAS TO BE PLANNED UP FRONT, DONE DEFINITIVELY. SOUNDS LIKE HE'S A HIGHLY FUNCTIONING INDIVIDUAL, RECEIVING CRANIOSPINAL RADIATION, 36 GRAY, THERE'S SOME LONG-TERM MORBIDITY ASSOCIATED WITH THAT. I THOUGHT THAT FOR A CASE LIKE THIS THE QUESTION THAT OFTEN COMES UP, HE HAD DISEASE IN HIS BRAIN, IF HE DIDN'T THE QUESTION WOULD BE COULD YOU JUST TREAT THE SPINAL CORD, AND AVOID THE BRAIN, AND THE ANSWER IS NO BECAUSE YOU'RE JUST TAKING RISKS. AND WE CANNOT MATCH UP RADIATION FIELDS LATER. SO THIS IS A GREAT CASE. IT'S VERY INSTRUCTIVE AND HAS A LOT OF CLINICAL DECISION. >> GREAT. NEXT. >> ABOUT TWO YEARS LATER HE HAD PROGRESSION AT C2, C3, RADIOGRAPHIC, NOT BIOPSIED AT THE TIME. IN CASE ANYONE WAS WONDERING. TREATED THEN WITH CARBOPLATIN, BEVACIZUMAB TIMES 6 CYCLES, AND BEVACIZUMAB MAINTENANCE FOR NINE MONTHS, AT THAT TIME EXPERIENCING SIGNIFICANT NEPHROTIC BRAIN PROTEINERIA, WITHIN A MONTH OR TWO OF STOPPING AGAIN EXPERIENCED PROGRESSION. THIS TIME AT THE SAME SITE AS WELL AS ENHANCING NODULES ALONG THE CORD. AT THAT TIME HE WAS SEEN AT AN OUTSIDE INSTITUTION, RECOMMENDED STEREO TACTIC SURGERY, BELOW, HE RECEIVED 24 GRAY OVER THREE FRACTIONS, SUBSEQUENT TO THAT WAS STARTED ON 24 HOUR INFUSION, GIVEN WEEKLY, SIX WEEKS OUT OF EVERY EIGHT. HE COMPLETED SEVEN CYCLES OF THAT, BUT HAD TO STOP DUE TO CYTOPENIAS, EUKO CYTIS AND OTHER ISSUES. IN 2017 HE EXPERIENCED PROGRESSION AT THAT POINT THE OPTION OF RESTARTING 5 FU WAS DISCUSSED, WE MET HIM AROUND THIS TIME, ADVISED HIM IN ADDITION TO RESTARTING 5FU HE COULD RESTART CARBOPLATIN AND BEVACIZUMAB, FOUR CYCLES, FOUR MONTHS LATER PROGRESSION, YOU CAN SEE ENHANCING DISEASE COMING UP. AT THAT TIME, CNS CANCER RECURRENCE TRIAL USING NIVOLUMAB THERAPY, RECEIVED TWO CYCLES AND WAS HAVING SYMPTOMS THAT WERE RELATIVELY AT BASELINE, ALTHOUGH THERE WAS A VERY IMPRESSIVE EMERGES OF OF NUMEROUS ENHANCING NODULES AND MASS EFFECT. LUMBAR PUNCTURE, NO MALIGNANT CELLS AND PARTICULAR INFLAMMATORY PROFILE. >> REMARKABLY WHILE ON NIVOLUMAB, HE FUNCTIONALLY GOT BETTER. HE WAS ABLE TO -- HE PREVIOUSLY HAD LIMITATIONS IN BEING ABLE TO SIT AND WORK AT A COMPUTER, WENT FROM BEING ABLE TO DO THAT FOR LESS THAN AN HOUR FOR THREE TO FOUR HOURS AT A TIME. SO WHEN HE RETURNED FOR FOLLOW-UP, AND PROVIDED THAT HISTORY, WE WERE ALL QUITE EXCITED UNTIL WE LOOKED AT THE IMAGING AND ACTUALLY SAW THAT THINGS WERE WORSE. WHICH IS WHY THE SPECTER OF MAYBE THIS WAS PSEUDOPROGRESSION, AND INFLAMMATORY, RATHER THAN TUMOR, WAS RAISED. >> IN 2018, HE COMPLETED THIRD CYCLE OF NIVO, ONE MONTH STOPPED, TREATED WITH STEROIDS DURING THAT TIME. THEN HE EXPERIENCED WORSENING MYELOPATHY, AND MRI SPINE IS REPEATED SHOWING AGAIN PROGRESSION OF DISEASE. SO, AT THE TIME BECAUSE OF CORD IMPINGEMENT, GIVEN SYMPTOMS, HE WAS DEBULKED, TISSUE SHOWED COPY NUMBER GAIN, FOUND ON THE ORIGINAL 2012 TISSUE ALSO. HE WAS STARTED ON ON LAPATINIB, HE WAS EXPERIENCING WORSENING IN THE BACK, FOUND TO HAVE INCREASED TUMOR COMPRESSION AT T-9 AND T10, THIS WAS RESECTED, TWO MONTHS LATER THERE IS MOSTLY ONE SITE OF PROGRESSION, THAT'S AT THE RIGHT CRANIAL CERVICAL JUNCTION, ALSO RESECTED, AND A MONTH LATER BEGINS HAVING WORSENING LEG WEAKNESS, BACK PAIN, SENSATION CHANGES, TREATMENT WAS DISCONTINUED, HE WAS TREATED WITH RADIATION, OVER 10 FRACTIONS, MOSTLY FOR PAIN, AND VORINOSTAT WAS STARTED. AFTER TWO MONTHS SCANS SHOWED CONTINUED PROGRESS, AT THAT TIME WE DISCONTINUED TREATMENT, REFERRED HIM FOR HOSPICE. >> THE REASON WE PICKED OUT THESE TWO CASES, INPUT FROM THE PANEL, I THINK IT'S THE TWO ENDS OF THE SPECTRUM OF SPINAL CORD EPENDYMOMA. IN ONE CASE CONSENSUS EN BLOC RESECTION, WITH A TUMOR CAPSULE INTACT, AND HERE WE HAVE ANOTHER SPINAL CORD EPENDYMOMA THAT HAD A VERY AGGRESSIVE AND MALIGNANT COURSE. AND THE QUESTION IS, IN PATIENTS WHO HAVE SPINAL CORD EPENDYMOMA, ARE THERE WAYS THAT WE CAN PREDICT IN ADVANCE WHO IS LIKELY TO HAVE THIS COURSE, OBVIOUSLY IN THIS SITUATION IT WAS OBVIOUS IT WAS DISSEMINATED. WE HAVE A MICROPHONE COMING. IN THE OTHER CASE, IT WAS -- SO MICHAEL. >> THE SECOND CASE IS NOT AN EPENDYMOMA. >> IT'S NOT? >> I DON'T KNOW WHAT IT IS. >> IT'S NOT. >> BASED ON HISTOLOGY? >> CLINICAL BEHAVIOR IS NOT THE SPINAL CORD EPENDYMOMA, PRETTY MUCH NEVER LOOK LIKE THAT. HOW MANY -- AS A GROUP, HOW MANY SPINAL CORD AND OTHER EPENDYMOMAS HAVE WE LOOKED AT AND HOW MANY TIMES HAVE WE SEEN HIGH LEVEL AMPLIFICATION OF MYC. >> TEN TIMES. >> SPINAL CORD TUMOR? >> YES. >> WE'VE LOOKED AT TONS, WE'VE NEVER SEEN IT ONCE. >> WE HAVE THREE. >> THEY TOLD ME IT'S RECURRING, WHAT COULD THIS BE? PATHOLOGIST SAID EPENDYMOMA, I SAID NO WAY. WE LOOKED TOGETHER, MOLECULAR PROFILING, SERIES OF 10 HIGHLY AMPLIFIED EPENDYMOMA IN THE SPINE. NO WAY. THIS IS ONE OF THE GRAY ISLANDS WE HAVE NOT DESCRIBED YET. >> (INAUDIBLE). >> SO WHAT I'M SAYING, THAT WE HAVE -- THIS IS TOTALLY NEW GROUP. IT MIGHT BE -- PROBABLY WE SHOULDN'T JUST CALL IT EPENDYMOMA BUT THIS IS DEFINITELY A NEW GROUP WHICH IS HIGHLY AMPLIFIED AND BY PATHOLOGISTS, WE HAVE THESE DISCUSSIONS, ARE CALLED EPENDYMOMA. >> KEN? >> ALL RIGHT. SO I WANT TO MAKE SURE, DO THESE CLUSTER ANYWHERE NEAR THE NINE STANDARD METHYLOME -- >> JUST REPEAT IT. >> JUST FOR THE RECORDING, THEY CLUSTER ON THEIR OWN, ON THE METHYLOME. SO AGAIN WE HAD A BIT OF A DISCUSSION YESTERDAY ABOUT CLASSIFICATION OF EPENDYMOMA, AND HOW DO WE RECONCILE THIS, SO THE PATIENT GETS A HISTOLOGIC DIAGNOSIS, AT WHAT POINT DO WE INTERVENE WITH MOLECULAR FINDINGS AND HOW DO WE THEN TRANSLATE THAT INTO DISCUSSION, PROGNOSIS AND TREATMENT. SOMEBODY, OH. >> I JUST WANTED TO ADD I HAVE A CASE EXACTLY LIKE THIS SITTING ON MY DESK RIGHT NOW. SO, THE PATIENT PRESENTED WITH MULTIPLE NODULES THROUGH OUTTHE PINE, NONE WERE INTRAMEDULLARY, ALL FROM THE DURA, NOT CONNECTED TO NERVE ROOTS, HISTOLOGICALLY LOOK LIKE THIS. LOOKING AT THE LITERATURE, MULTIPLE CASE REPORTS OF THESE INTRADURAL EPENDYMOMA-LIKE TUMORS, WITH MULTIPLE NODULES EXACTLY LIKE THIS. SO, IT COULD BE A NEW ENTITY THAT'S NOT BEEN DESCRIBED BEFORE. >> SO A PSEUDOROSETTE FORMING, MYC AMPLIFIED EPENDYMOMA? >> IT HAS ALL THE FEATURES. GFAP ACCENTUATION, EME-LIKE STAINING, CIRCUMSCRIBED, NOT INFILTRATING INTO THE SURROUNDING REGION. >> RICHARD, LET'S WAIT FOR THE MICROPHONE. IF IT WAS FOOTBALL SEASON YOU COULD THROW IT. >> YEAH, THAT'S A JOKE. >> DAVID WILL TELL YOU THIS, HE'S THE EXPERT, YOU KNOW, PSEUDOROSETTES ARE NOT AN EXCLUSIVE FEATURE. WE'RE LEARNING THAT. CONFLATING THE ISSUE OF THERAPEUTIC VERSUS CLASSIFICATION WHILE THEY ARE LINKED IS PROBLEMATIC. THE FIRST QUESTION IS WHAT IF THIS IS AN ENTITY, AND THEN THE QUESTION IS WHAT DO WE DO WITH THAT AS AN ENTITY, BUT IF WE CONTINUE TO CONFLATE IT WE'LL BE CAUGHT IN THIS MIDDLE GROUND OF CONTINUING TO PERPETUATE THE CONCEPT THESE ARE PROBABLY GOING TO RESPOND TO THE SAME THERAPIES, AS WE SEE IN CLASSIC EPENDYMOMAS SO WE HAVE TO SEPARATE THE TWOI AND DECIDE WHAT WE DO WITH THESE PATIENTS. THIS IS NOT WHAT WE CURRENT UNDERSTAND HISTOLOGICALLY IS AN EPENDYMOMA, AND MOLECULARLY, HOW DO WE CLASSIFY. >> DAVID? >> THANK YOU. SO, REGARDING THE ISSUES OF NOMENCLATURE AS WE ENCOUNTER NEW ENTITIES LIKE THIS WHICH HAVE A HISTOLOGIC PATTERN WHICH I THINK LOOKS LIKE EPENDYMOMA, I THINK BASED ON HISTOLOGY I SEE, THAT WAS A REASONABLE DIAGNOSIS, BUT CLEARLY DEALING WITH A DIFFERENT TYPE OF DISEASE. METASTATIC AT THE OUTSET, WITH A DISTINCTIVE GENETIC ALTERATION, MYC AMPLIFICATION. THOSE WHO IN COMBINATION SET IT APART FROM WHAT WE UNDERSTAND TO BE THE MORE TRADITIONAL SPINAL EPENDYMOMA, IN THE FIRST CASE THIS MORNING. NOW, SINCE W.H.O. IN 2016 GROUP MADE RECOMMENDATIONS ABOUT HOW TO DEAL WITH THESE TYPES OF TUMORS, IN THE FORM OF INTEGRATED DIAGNOSIS, WHERE COMBINATION OF FEATURES IS BROUGHT TOGETHER TO DEFINE A DISEASE, HISTOLOGY IS PART OF THAT, AND I THINK THAT NEEDS TO BE PART OF THAT FOR THE MOMENT. AND THE GENETIC ALTERATION IN THIS CASE MYC AMPLIFICATION WOULD BE USED ALONGSIDE HISTOLOGY TO MAKE AN INTEGRATED DIAGNOSIS. I THINK IT'S EXTREMELY INTERESTING THAT THESE TUMORS FORM THEIR OWN METHYLOMIC GROUP. AND IT'S SORT OF ENTITY GOING DOWN THE ROAD WE WOULD CLASSIFY SEPARATELY FROM OTHER EPENDYMOMAAL DISEASES, DEFINING GENETIC ALTERATION WHETHER THAT'S THE MYC AMPLIFICATION OR METHYLOMIC GROUPING THAT HELPS DEFINE IT. >> I'LL ASK DAVID AND KEN TO COMMENT ON THE 2020 CONSENSUS CONFERENCE YOU THINK IT IS TIME TO USE N MYC AMPLIFICATION IN SPINAL CORD TUMORS THAT LOOK LIKE EPENDYMOMA, FOR THE SUBCLASSIFICATION, METHYLOME IS NICE BUT UNLIKELY IN WIDESPREAD USE BECAUSE OF COST AND CLIA CERTIFICATION. ARE YOU WILLING, AGAIN IT WILL BE SIX OR SEVEN YEARS AFTER THAT BEFORE YOU HAVE ANOTHER BITE AT THE APPLE. >> SO JUST TO MAKE A COUPLE COMMENTS. SO, THE CYCLE HAS BEEN LONG BETWEEN ADDITIONS TO W.H.O. CLASSIFICATION BUT THE SIGNS AT THE MOMENT IT'S GOING TO SPEED UP. 2020 IS A FOUR-YEAR GAP FROM 2016, I THINK WE DO NEED FREQUENT UPDATES IN ORDER TO ACCOUNT FOR THE BIOLOGIC ADVANCES, OUR UNDERSTANDING OF THE MOLECULAR BASIS OF THE DISEASE. TO ANSWER YOUR QUESTION ABOUT THIS ENTITY, I HOPE BY 2020 WE'LL HAVE IN FRONT OF US THE STUDIES FROM HEIDELBERG AND PERHAPS ELSEWHERE ABOUT THIS ENTITY. AND, YOU KNOW, I THINK IT WILL BE NICELY DEFINED BY COMBINATION OF HISTOLOGY AND THE GENETIC ALTERATION, MYC N AMPLIFICATION, AS THE POSITIVE EPENDYMOMA IN THE 2016 CLASSIFICATION IS DONE AT THE MOMENT. I DON'T THINK YOU WOULD NEED TO DEFINE ITS METHYLOMIC GROUP TO PUT IT IN CLASSIFICATION AND THERE BY WARRANT THAT APPROACH TO DIAGNOSIS. I THINK IT WOULD SIT IN THERE VERY NICELY, WITH THE COMBINATION OF HISTOLOGY AND THE MYC N AMPLIFICATION. >> KEN? >> YEAH, THIS CASE ILLUSTRATES SEVERAL FEATURES, ONE IS WHENEVER SOMETHING DOES NOT FIT WITH STANDARD SPINAL CORD EPENDYMOMA, THAT WE SHOULD STRONGLY CONSIDER SOMETHING LIKE METHYLATION PROFILING TO CLASSIFY, WHEN IT'S NOT FITTING WITH THE USUAL COURSE OF EVENTS, NUMBER ONE. NUMBER TWO, I'M NOT SURE I WOULD BE AS NIHILISTIC ABOUT PROFILING IN W.H.O. AND I HOPE WE'RE NOT NILISTIC. IT CAN BE DEDUCED FROM METHYLATION TEST. MY CONCERN DEFINING AS MYC N WE NEED TO MOVE FORWARD FROM SINGLE GENE DEFINITIONS OF ENTITIES. I'M GOING ASK ONE FINAL QUESTION, WE WANT TO MOVE TO THE PEDIATRIC CASE BUT I WOULD ASK DR. MERCHANT, IF WE HAD -- IF THIS PATIENT PRESENTED WITH JUST A SINGLE EXTRAMEDULLARY NODULE COMPLETELY RESECTED AND YOU GOT BACK THAT IT'S THIS NEW DISEASE THAT WE DON'T HAVE AN ACRONYM FOR, N MYC AMPLIFIED, PSEUDOFORMING SPINAL CORD TUMOR, MANY CASES WERE EITHER PRESENTED AT DISSEMINATION, WOULD YOU HAVE PROCEEDED IN THAT CASE WITH CRANIAL SPINAL RADIATION? >> I THINK IT'S TOO DIFFICULT TO SAY. FOR THE CLASSIC ANAPLASTIC EPENDYMOMA THAT'S RESECTED, DEBATED WHETHER TO GIVE RADIATION IN THOSE CASES. IN THE PAST, BASED ON THE AGGRESSIVE FEATURES PATIENTS WERE RADIATED, BUT I DON'T THINK THAT WAS DONE BY EVERYONE AND I DON'T THINK IT'S INDICATED. THIS DID NOT ACT LIKE A HIGH GRADE SPINAL CORD TUMOR BECAUSE THOSE PATIENTS SUCCUMBED TO THEIR DISEASE FAIRLY QUICKLY SO THIS IS SOMETHING IN BETWEEN THERE. DOES RADIATION EVEN WORK IN THIS DISEASE? WE DON'T HAVE AN ANSWER. >> WELL, I MEAN, IT WORKED FOR HIM FOR TWO YEARS, IT KEPT TUMOR ABATED. I'LL ASK ROGER, IF YOU SEE A PATIENT LIKE THIS, WHO HAS A DISEASE THAT WE'RE DEFINING AS THIS N MYC AMPLIFIED METHYLOME GRAY ZONE -- >> I THINK ONE OF THE THINGS AS A DISCIPLINE, NOT EVERYBODY DESERVES TO FIT ON A PROTOCOL OR SHOULD BE INCLUDED IN A PROTOCOL. AND IF YOU PUT PATIENTS, TREMENDOUS MOLECULAR OUTLIERS ON DIFFERENT PROTOCOLS, YOU JUST MESS WITH RESULTS FOR MAIN GROUP THAT'S HOMOGENOUS AND MAKE NO PROGRESS WITH THE GROUP THAT'S OUTLYING. MY MESSAGE IS THIS PATIENT SHOULD NEVER BE THOUGHT OF BEING TREATED AS AN EPENDYMOMA, IT'S ITS OWN ENTITY. ANSWERING YOUR QUESTION I THINK WE HAVE TO LOOK AT THE DATA VERY CAREFULLY. IF EVERY PATIENT WITH THIS ENTITY HAS DISSEMINATED DISEASE AND IF EVERY PATIENT WITH THIS ENTITY AFTER FOCAL RADIATION HAS DIED IT WOULD MAKE A LITTLE BIT MORE SENSE TO DO SOMETHING DIFFERENT, AND MAYBE THAT DIFFERENT IS PROPHYLACTICALLY SPINAL, MAYBE IT ISN'T. I DON'T KNOW IF THIS IS RADIOSENSITIVE BUT I THINK THE MAIN PART IS YOU JUST GOT TO LOOK AT THE DATA VERY CAREFULLY AND FACTOR IN THE CLINICAL DATA BEFORE KNEE-JERKING THAT YOU'RE GOING TO GRAB THIS WHOLE GROUP OF PATIENTS AND EXPOSE THEM TO MORBIDITY OF CRANIOSPINAL RADIATION. I NEED TO KNOW MORE ABOUT THE ENTITY, BUT IF EVERYONE DIEES OF DISSEMINATED DISEASE YOU WANT TO GO THAT WAY, THAT'S FINE. I DON'T FEEL STRONGLY ONE WAY OR THE OTHER. >> CHRISTIAN? >> WHICH IS INDEED THE CASE. ALL OF THESE TEN PATIENTS REALLY PROGRESSED FAST, THEY HAD METASTATIC DISEASE, EXACTLY WHAT WE HAVE JUST SEEN HERE. THIS REALLY SEEMS TO BE ONE PATTERN. >> HOW WERE THEY TREATED? HOW MANY OF THOSE HAD CRANIOSPINAL AND STILL DEVELOPED METASTATIC DISEASE? HOW MANY WERE TREATED ONLY WITH FULCRUM RADIATION, HOME TREATED WITH NOTHING AND DISSEMINATED, HOW MANY DISSEMINATED AT THE TIME OF DIAGNOSIS? THOSE ARE THE FACTORS TO GET FACTORED IN. WHEN YOU PUT THAT TOGETHER USING CLINICAL STUFF AS A VARIABLE, NOT JUST OH BY THE WAY THEY GOT TREATED, AND FORGET ABOUT IT, AND SAY WHAT THE NATURAL HISTORY IS, THEN YOU CAN DECIDE FOR THE NEXT TEN OF THESE, THE NEXT TWENTY, YOU'LL DO IT IN ONE WAY TO TRY TO GET SOME KIND OF ANSWER. >> ONE PROBLEM HERE IS THAT THEY ARE ALL TREATED LIKE THIS PATIENT HERE, THEY GOT ALMOST EVERYTHING. SO THIS MAKES IT OF COURSE VERY DIFFICULT TO REALLY PREDICT WHICH OF THE THERAPIES IS THE BEST ONE AND WHAT WE SHOULD DO BUT THEY ARE ALL SIMILAR TO THIS, EXACTLY TO THIS CASE. >> RIGHT. AND, AGAIN, AT THE TIME WE DIDN'T KNOW ANYTHING ABOUT THIS BEING A SEPARATE ENTITY, BUT GAVE THE PATIENT THE THERAPIES THAT WE KNEW AND TRIED, OBVIOUSLY. THERE WAS A -- WITH HIS CONSENT OF COURSE. IT DOES SPEAK TO THE NEED FOR US TO HAVE ON A REGISTRY FOR THESE TYPES OF THINGS TO COMPILE THE DATA. NICK? >> TWO COMMENTS. AT LEAST IN MICE, WITH DISSEMINATED EPENDYMOMA-LIKE DISEASE, 5FU WORKS BETTER WITH RADIATION THAN SEPARATELY. I MEAN IT'S ACTUALLY -- IT REALLY IS QUITE EFFECTIVE ACTUALLY WHERE THE TWO ENTITIES SEPARATELY DON'T WORK VERY WELL. I THINK GOING FORWARD, WE SHOULD ACTUALLY CONSIDER THAT FOR ACTUALLY SOME OF THESE PATIENTS. THE SECOND IS IF YOU'RE TO DO LPs ON THESE TYPES OF PATIENTS, WHY AREN'T YOU LOOKING FOR FREE DNA ON THEM? BECAUSE THIS IS -- YOU KNOW, A CLASSIC PATIENT, YOU COULD POTENTIALLY FOLLOW DURING THOSE TWO YEARS, WHERE YOU HAD TIME AFTER THE RADIATION TO ACTUALLY FOLLOW. I MEAN, I THINK FOR A LOT OF US, PARTICULARLY WHERE YOU ACTUALLY HAVE SOMETHING THAT'S AMPLIFIED, YOU ACTUALLY CAN FIND STUFF IN THE CSF, AND DOING IT FOR CELLS IS JUST A COMPLETE WASTE OF TIME. YOU REALLY SHOULD CONSIDER WHETHER YOU SHOULD MOVE TO NEW TECHNOLOGY IF YOU'RE GOING TO DO IT. >> WE HAVE A PROGRAM DEVELOPING AND WE HAVE A CSF SAVED, SO -- BUT, AGAIN, PUTTING THAT IN THE CONTEXT OF HOW TO FIT THAT IN TO TREATMENT, IT'S GOING TO REQUIRE CAREFUL ANALYSIS OF NOT ONE PATIENT BUT A WHOLE SERIES. WE NEED TO MOVE ON TO THE PEDIATRIC CASE. I THINK THAT WAS A GREAT DISCUSSION, AND REALLY APPRECIATE EVERYBODY'S INPUT. SO, ASK ELIZABETH FINCH FROM CHILDREN'S NATIONAL. >> ALL RIGHT. I'LL TRY TO TALK FAST. SO WE HAVE A 2-YEAR-OLD MALE, HISTORY OF MILD SPEECH DELAY, PRESENTED AFTER FALLING OFF THE BED WITH HEADACHES, VOMITING, ON RETROSPECT PARENTS NOTED HE WAS IRRITABLE, ABNORMAL GAIT TWO WEEKS, HEAD CT WAS OBTAINED. IN THE E.R. HE DID DEVELOP SOME ALTERED MENTAL STATUS, INTUBATED AFTER CLONIC SEIZURE, LOADED WITH ANTI-EPILEPTICS. AS FAR AS HISTORY GOES, PRETTY BENIGN HISTORY, NO CANCERS IN THE FAMILY. HIS INITIAL EXAM, WHEN HE ARRIVED TO CHILDREN'S AT THAT POINT, SEDATED, NEUROMUSCULAR BLOCKERS, LIMITED EXAM, DCF WAS 5, EXTENSOR POSTURING AND BILITERAL BABINSKI. THIS IS INITIAL HEAD CT FROM OUTSIDE HOSPITAL WHERE HE PRESENTED. THERE IS A LARGE PARTIALLY CYSTIC, PARTIALLY SOLID MASS. THERE IS MIDLINE SHIFT, ABOUT 1.5 CENTIMETERS, ALSO NOTED TO BE SOME UNKAL HERNIATION, TRANSFERRED TO OUR FACILITY, THIS MRI WAS DONE THE FOLLOWING DAY. YOU CAN SEE IT'S A PRETTY VASCULAR TUMOR, VERY LARGE, THERE IS A LITTLE BIT OF DECOMPRESSION FROM EDB BUT STILL SOME HYDROCEPHALUS. THAT'S JUST SOME ADDITIONAL IMAGING. I DON'T KNOW IF WE WANT TO DISCUSS WHAT PEOPLE WOULD DO NEXT. >> LET ME ASK. MICHAEL? >>> YOU KNOW, IT'S JUST ABCs, RIGHT? FOR THE NON-SURGEONS HERE, ABCs, AIR WAY, BREATHING CIRCULATION, HYPERVENTILATED, OPERATING ROOM, MANNITOL, LEFT FRONTAL EVD, FLIPPED AFTER LARGE DOSE OF STEROIDS FOR CRANIAL. LARGE EPENDYMOMAS IN YOUNG CHILDREN, FOR SOME REASON THEY ALL GO DOWN TO THE AREA OF AROUND THE VEIN OF GALEN, NARROW LIKE A TRIANGLE, AT THE END OF A LONG CASE DOING THE DANGEROUS PART THAT'S STUCK TO GALEN, STUCK TO INTRACEREBRAL VEINS. THAT LOOKS LIKE IT'S CYSTIC, BUT I'M NOT SO SURE THAT WILL BE CYSTIC. I THINK THE WHOLE THING MIGHT BE SOLID, THAT'S A LONG DAY. IF IT REALLY IS THE CASE, YOU SHOULD GO IN AND TAKE OUT 90%. IF YOU'RE TIRED, LEAVE THAT LITTLE BIT AT THE END STRUCK TO THE VEINS AND DO IT LATER AFTER YOU REST. >> CAN WE GO BACK FOR A SECOND? THAT ONE. I THINK THIS IS -- OBVIOUSLY THIS IS GOING TO BE A SURGICAL PROCEDURE, KEEP THE KID ALIVE, GET THE SHIFT DONE, TRY TO REMOVE IT. WHEN YOU LOOK AT THIS, WE KNOW WE'RE AT AN EPENDYMOMA CONFERENCE, IT'S AN EPENDYMOMA, IT COULD BE ABOUT ANYTHING. IT'S STILL AT THIS ENTITY. IT'S CERTAINLY SHIFTED. IT'S NOT LIKELY TO BE ONE OF THE THINGS WE LIKE TO SEE LIKE A INFANTILE GLIOMA WITH LITERAL CYST AND MEDIAL ENHANCEMENT. WE LOOK FOR THOSE BECAUSE THOSE THEORETICALLY ARE SURGICALLY CURABLE. AS TERRIBLE AS THEY LOOK, THE CHILD IS YOUNG, SOMETIMES WE ARE FORTUNATE AND IT'S NOT AS AGGRESSIVE. IN THIS CASE PRETTY SURE EVERYONE THOUGHT THIS WAS NOT GOING TO BE THE BENIGN VARIANT GLIOMA SPECTRUM BUT AGGRESSIVE. WHETHER IT WAS GOING TO BE A MALIGNANT EPENDYMOMA, WHATEVER YOU WANT TO CALL IT, OR FALL INTO AMORPHOUS EMBRYONAL TUMOR TYPE, NOBODY KNEW. WE LOOKED TO BE SURE HOW SICK HE WAS TO MAKE SURE HE WASN'T DISSEMINATED BECAUSE IF THIS WAS WIDELY DISSEMINATED ONE OF THE QUESTIONS IS HOW AGGRESSIVE DO YOU WANT TO BE AT ALL IN THIS CASE. GIVEN THE AGE AND EVERYTHING ELSE, I THINK AS IT WAS AN ISOLATED LESION, THE SURGEON DID WANT TO BE AGGRESSIVE. >> IF THEY HAD A LOWER CUT, THESE ONES THAT POINT AT VEIN OF GALEN, LIKE AN ARROW POINTING AT GALEE ALMOST ALWAYS EPENDYMOMAS, I'VE SEEN THIS PATTERN A BUNCH OF TIMES. >> CARRY ON. >> SPINAL IMAGING WAS NEGATIVE. SO THEY DID PLACE THE EBD, NEXT DAY WITH OCCIPITAL CRANIOTOMY. >> DAVID? COULD YOU TALK ABOUT THE PATHOLOGY? >> THANK YOU. SO WE'RE LOOKING HERE AT H&E SECTION, NEOPLASTIC PROCESS COMPOSED OF FAIRLY DENSE CELLS IN GROUPS, AND INTERVENING FIBRO VASCULATURE, DIFFICULT TO TELL HOW MUCH MICROVASCULAR PROLIFERATION, A COUPLE GROUPS OF ENDOTHELIAL CELLS, LIKED HYPERPLASTIC, PERHAPS HIGH POWER VIEW WILL LET US LOOK AT THE CELLS. THANK YOU. SO, INTERESTINGLY IT HAS THE LITTLE ROUND EOSINOPHILIC GLOBULES. BUT I ALSO NOTE DYSTROPHIC CALCIFICATION, I ALSO NOTE THAT THE PSEUDOROSETTES AND THE TUMOR NOT SO APPARENT AS IS THE SPINAL TUMORS, CHARACTERISTICS FOR SUPER TENTORIAL EPENDYMOMA. SEEN HERE WITH THE RED ARROW, THESE ARE VERY VARIABLE TUMORS IN TERMS OF MITOTIC ACTIVITY BUT IN MY EXPERIENCE MANY OF THE SUPER TENTORIAL ARE HIGH GRADE WITH HIGH MITOTIC COUNT WARRANTING GRADE 3. HERE'S THE COMBINATION OF PUNCTATE EMA IMMUNOACTIVITY IN CYTOPLASM OF MANY TUMOR CELLS. SOMETIMES YOU CAN SEE CIRCULAR ARRANGEMENT, IN THE CYTOPLASM, SLIGHTLY BROADER THAN THE FINE DOTS, A MORE SPECIFIC FINDINGS, A MARKER OF GROWTH FRACTION IN THE TUMOR, THIS IS VERY HIGH. >> SO AT THAT TIME IT WAS -- DIAGNOSIS WAS FAVORING GREAT 3 ANAPLASTIC EPENDYMOMA, THEY WEREN'T 100% SURE BUT THAT WAS OUR PRELIMINARY DIAGNOSIS. AND SO THE QUESTION WAS WHAT TO DO AFTER THAT. >> SO NOW KNOWING WHAT WE KNOW, DAVID, WOULD YOU FEEL COMFORTABLE CALLING THIS AN EPENDYMOMA? TREATING IT? WOULD YOU DO ADDITIONAL MOLECULAR TESTING? >> THANK YOU. YES, SO THE APPROACH WOULD BE TO WORK THIS UP FULLY FROM MOLECULAR PERSPECTIVE, LOOKING FOR FUSIONS, IN TIME WE WILL DO METHYLATION ANALYSIS ON THIS. THE TUMOR WOULD GET GENOMIC ANALYSIS, LOOKING FOR SOME OF THE TYPICAL SUPER TENTTORIAL GENETIC ALTERATION. >> LET ME ASK, THIS IS AN EXTRAORDINARILY HIGH PROLIFERATIVE INDEX. AND DOES THAT CHANGE YOUR THOUGHT PROCESS ABOUT THE LIKELIHOOD THAT THIS IS A TRUE MOLECULAR CARD-CARRYING EPENDYMOMA, OR IN THE PEDIATRIC -- WE RARELY SEE ANYTHING THIS HIGH IN ADULT EPENDYMOMA, AT LEAST AT DIAGNOSIS, SOMETIMES ON RECURRENCE THEY ARE MORE AGGRESSIVE. >> SO OBVIOUSLY WE'RE SEEING A SNAPSHOT IN THESE IMAGES OF BOTH IMMUNO, FOR GFAP AND OTHER HIGH IN MY EXPERIENCE, SOME SUPERTENTORIAL EPENDYMOMA. IT TENDS TO VARY IN A WAY FROM VERY HIGH LEVELS TO REALLY QUITE LOW LEVELS ACROSS THE TUMOR, VERY HETEROGENEOUS IN THE WAY YOU WOULDN'T EXPECT FOR EMBRYONAL TUMOR. CELL DIFFERENTIAL IN THE UNDIFFERENTIATED CYTOLOGY COULD DO, BUT I'M ASSUMING YOU'RE SHOWING GFAP CHARACTERISTIC OF EPENDYMOMA, LACK OF NEURONAL MARKERS WOULD BE EXPECTED FOR THE EMBRYONAL TUMOR. >> ROGER, BASED ON THIS WOULD YOU GO FORWARD WITH EPENDYMOMA THERAPY OR WAIT FOR -- >> FIRST OF ALL WE HAVEN'T SEEN DEGREE OF RESECTION, SO I DON'T THINK WE CAN MAKE ANY DECISION OF WHAT WE WOULD DO. BUT WITHIN HIGH MITOTIC INDEX, ANAPLASTIC OR SOMETHING THAT FITS INTO THE ANAPLASTIC EPENDYMOMA DISSUADE ME? NOT AT THIS AGE RANGE AT ALL. WE SEE VERY AGGRESSIVE TUMORS. IT MAY BE MOLECULARLY SOMETHING DIFFERENT BUT CERTAINLY THE GOING BET UNTIL WE GOT MOLECULAR TEST BACK WOULD BE THAT IT PROBABLY IS A MALIGNANT ANAPLASTIC EPENDYMOMA IN A YOUNG CHILD WHICH ARE VERY AGGRESSIVE. >> OKAY. ELIZABETH? >> THERE WAS A SECOND SURGERY DONE, GIVEN INITIAL PATHOLOGY. IT WAS A GROSS TOTAL RESECTION. AS YOU CAN SEE ON THE RIGHT-HAND SIDE. >> THE SURGEON WAS VERY DISAPPOINTED IN THE INITIAL SURGERY, THOUGHT HE GOT MORE OUT. THOUGHT A LOT OF THAT MIGHT JUST BE NECROSIS BUT WAS ABLE TO COME BACK IN AND BE MUCH MORE AGGRESSIVE THE SECOND TIME. >> AND WITH MORE TISSUE, WE WERE ABLE TO SEND IT TO SAINT JUDE FOR A SECOND OPINION, AND THEY FELT IT WAS ALSO LIKELY AN ANAPLASTIC EPENDYMOMA. FOUNDATION MEDICINE WAS ALSO SENT. YOU CAN SEE THAT THERE. >> OKAY. DR. MERCHANT, WHAT WOULD YOUR APPROACH BE? >> GO BACK. >> SORRY. >> DON'T DO THAT! [LAUGHTER] >> SO FIRST OF ALL, WE WOULDN'T BE IN A RUSH TO TREAT THIS PATIENT. I'M SAYING THAT BECAUSE OFTEN FAMILIES ARE PRESSED TO START RADIATION THERAPY WITHIN 30 DAYS. THERE'S NO EVIDENCE AT LEAST IN OUR LITERATURE THAT THAT'S A REQUIREMENT, AND IF YOU UNDERSTAND THE ELIGIBILITY CRITERIA FOR THE CURRENT AND PAST COG PROTOCOLS FOR EPENDYMOMA, WE ALLOW 56 DAYS FROM SURGERY TO TIME OF ENROLLMENT AND THREE WEEKS TO START TREATMENT. I'M SAYING THAT BECAUSE THERE'S USUALLY A TREMENDOUS AMOUNT OF BRAIN SHIFT IN THESE YOUNG PATIENTS, AND IT'S WORTH FOLLOWING THEM CLOSELY FOR A FEW WEEKS TO ALLOW THE TUMOR BED TO COLLAPSE AND THE BRAIN TO REPOSITION ITSELF. THAT HAS A LOT TO DO WITH TARGETING FOR THE RADIATION THERAPY, THE CONCEPT TO TREAT THE SMALLEST VOLUME. WE DISCUSSED THIS YESTERDAY, THERE WAS MENTION ABOUT THE BURDEN THAT THESE PATIENTS SUFFER WHEN THEY RECEIVE RADIATION THERAPY. IT'S BEEN MORE THAN 20 YEARS SINCE WE TREATED THE PREOPERATIVE VOLUME FOR THESE PATIENTS, WE'RE TREATING POSTOPERATIVE TUMOR BED HERE AND JUST THAT EDGE OF THE BRAIN. THE INPUT FROM THE NEUROSURGEON IS KEY HERE, DISCUSSING POINT OF ATTACHMENT AS MICHAEL TAYLOR MENTIONED, YOU KNOW, HE UNDERSTANDS WHERE THE POINT OF ATTACHMENT MIGHT BE HERE AND WE CAN USE THAT INFORMATION WHEN WE TARGET FOR TREATMENT. SO WE WOULD OUTLINE THE EDGE OF THE TUMOR BED USING PREOPERATIVE IMAGING, AND THE POSTOPERATIVE SCANS AS WELL, AND WE WOULD ADD A 5-MILLIMETER MARGIN, THE CURRENT CLINICAL TARGET VOLUME MARGIN ON THE CURRENT COG, SURVEY STUDY. THIS PATIENT WOULD RECEIVE 59.4 GRAY SO 33 FRACTIONS OF RADIATION THERAPY, THERE WOULDN'T BE A VOLUME REDUCTION, AFTER 54 GRAY, BECAUSE THERE'S NOT WHAT WE WOULD CONSIDER CRITICAL NORMAL TISSUE STRUCTURE LIKE THE BRAINSTEM, SPINAL CORD OR OPTIC CHIASM IN THIS VOLUME. AND WHILE EVERY PART OF THE BRAIN IS IMPORTANT, THIS IS PROBABLY AN AREA OF THE BRAIN WHERE IT'S A LITTLE FORGIVING, MORE FORGIVEN FOR US TO DELIVER TREATMENT HERE BUT WE HAVE TO BE ABSOLUTELY SURE OF THE VOLUME THAT WE'RE TREATING AND THAT INTERACTION BETWEEN THE CLINICAL TEAM TO UNDERSTAND THE POINT OF ATTACHMENT IS VERY IMPORTANT. >> PROTON OR PHOTON? >> I THINK THE PATIENT COULD BE TREATED WELL EITHER WAY. OBVIOUSLY PROTON THERAPY WILL REDUCE INTEGRAL DOSE, IT WILL MINIMIZE DOSE TO NORMAL TISSUES, AND OUR MODEL SUGGESTS THERE'S A POTENTIAL BENEFIT THERE. >> DR. PACKER? >> YEAH, I THINK THIS IS REALLY A DIFFICULT ONE. WE TALKED ABOUT THIS YESTERDAY BECAUSE OF THE AGE. AND THE SIZE. EVEN WITH PROTON. THIS WAS A LONG CONVERSATION WITH THE FAMILY OF WHETHER WE START CHEMOTHERAPY AS PER POSSIBLY THE GRUNDY REGIMEN OR SIMILAR REGIMEN OR GO AHEAD WITH RADIATION THERAPY. I THINK I WAS OUTVOTED ON THIS ONE BECAUSE I WOULD HAVE GONE CHEMOTHERAPY FIRST ON THIS TO TRY TO SEE IF THIS IS ONE OF THESE 30% OR SO THAT WE COULD POTENTIALLY CONTROL WITH CHEMOTHERAPY, AND MY ONLY COMMENT TO TOM ABOUT WAITING UP TO 56 DAYS, THE REASON TO DO THAT SECOND SURGERY IN MANY CASES IS TO GET THIS DOWN TO MINIMAL RESIDUAL DISEASE, AND WE ARE ALWAYS WORRIED WITH THAT HIGH MITOTIC INDEX IF WE WAIT TOO LONG THEN WE WOULD BE A REGROWTH AND NEED FOR THIRD SURGERY BEFORE YOU START RADIATION. SO I'M NOT SURE AS A CLINICIAN I'M REAL COMFORTABLE WITH 56 DAYS, AND I'D LIKE TO GET THESE KIDS IF WE'RE GOING TO GO TO RADIATION AS EARLY AS POSSIBLE, AND IF WE'RE NOT GOING TO GO TO RADIATION CLEARLY AS SOON AS THEY RECOVER TO START CHEMOTHERAPY. BUT I -- IN OUR DEMOCRATIC SYSTEM AT CHILDREN'S LOST THAT BATTLE, HE WENT TO RADIATION THERAPY. >> LET ME ASK A QUESTION ABOUT UPFRONT CHEMOTHERAPY APPROACH, IN A SITUATION WITH NO MEASURABLE DISEASE WHAT METRIC WOULD YOU USE? >> THAT HE'S ALIVE A YEAR LATER WITH NO DISEASE. THAT'S MY ONLY METRIC, ALIVE AND NO DISEASE. I DON'T CARE ABOUT ANYTHING ELSE TO BE BLUNTLY HONEST. >> OKAY. >> HE DID GET PROTON THERAPY, UNIVERSITY OF MARYLAND, DID WELL FIVE MONTHS, FOLLOWED WITH CEMENTER MRI SCANS UNTIL WE SAW THIS NODULE AT T1. SO AT THAT POINT WE DISCUSSED DIFFERENT TREATMENT OPTIONS WITH THE FAMILY. AND THEY DECIDED TO ENROLL IN A REMIND TRIAL, AVAILABLE AT CHILDREN'S, WHICH USES T CELLS, TARGETED AGAINST THREE COMMON ANTIGENS ON TUMORS. THEY TAKE 6 TO 8 WEEKS TO EXPAND, SO IN THE MEANTIME AFTER HIS CELLS WERE COLLECTED HE RECEIVED I.T. AND HAD ANOTHER MRI PRIOR TO RECEIVING T CELLS AND AT THAT POINT HE HAD MULTIPLE LESIONS, BOTH IN THE BRAIN AND THE SPINE. YOU CAN SEE ON THE SPINAL IMAGING T1 FLARE, RATHER LARGE LESION, SO THE DECISION WAS MADE AT THAT POINT TO GO AHEAD AND D BULK BECAUSE IT WAS STARTING TO IMPINGE ON THE SPINAL CORD. >> GO BACK. >> THE OTHER, THIS IS DR. WONG'S PROTOCOL WITH CATH BALLARD AT CHILDRENS. MY RECOMMENDATION NOT TO FLIP HIM AFTER THAT SURGERY ON THE THORACIC AREA TO ACTUALLY GO BACK IN WITHIN A WEEK AND TRY TO REMOVE THE TWO FRONTAL LESIONS TOO. IF YOU WERE GOING TO THINK THAT THIS T CELL APPROACH OR ANY KIND OF APPROACH WAS GOING TO BE OF BENEFIT. THE FAMILY WAS GOING TO GO AHEAD WITH THAT MULTIPLE RESECTION APPROACH, BUT HE HAD -- JUST DIDN'T FEEL WELL AFTER THE SURGERY, IN THE THORACIC AREA. THE RATIONALE IF T CELLS WORK AND YOU GOT INTO SWELLING WE MIGHT RUN INTO TROUBLE WITH CORD PROBLEMS. THAT'S WHY IT WAS RENT OVER THE THORACIC LESION BUT WE WOULD HAVE LEFT -- MOVE THE OTHER TWO. THIS IS A VERY UNUSUAL PATTERN FOR EPENDYMOMA RELAPSE >> HE DID RECEIVE T CELLS LAST WEEK, AND HAS TOLERATED THEM WELL THUS FAR. >> DO WE HAVE PATHOLOGY ON THE SPINAL CORD? >> (INAUDIBLE). >> INTRAVENOUS, PATHOLOGY THE SAME. >> T CELLS PRIOR TO SURGERY? NO? OKAY. >> YOU SHOULD HAVE GIVEN T CELLS BEFORE SURGERY AND THEN GONE IN AND DONE THE SURGERY AND LOOKED FOR THEM IN THE SPECIMEN, RIGHT? >> IT WOULD HAVE BEEN NICE BUT ACTUALLY WE WANTED TO KEEP HIM ALIVE AND WALKING. THESE MINOR LEAGUE DECISIONS. THE OTHER THING TO BRING OUT, IF YOU TAKE A LOOK AT THAT KID THAT HAS GONE -- CAN WE SHOW THAT BRAIN AGAIN? MY CONCERN IN THIS CHILD, WE'VE HAD EPENDYMOMAS THAT HAVE GONE SYSTEMIC, LYMPH NODES, IT'S ACTUALLY ONCE THEY START GOING INTO THE MENINGES LIKE THAT THAT I WORRY THEY ARE GOING TO GO EXTRANEURAL, THAT'S BEEN OUR EXPERIENCE, WIDELY DISSEMINATED EPENDYMOMA MAY NOT ONLY BE A CNS DISEASE. >> DID YOU LOOK AT THE -- WHAT WAS THE IMMUNE COMPLEMENT PRESENT IN THE ORIGINAL TISSUE? >> I'D HAVE TO ASK GENE. I DON'T THINK THAT WAS LOOKED AT THE IMMUNE COMPLEMENT AT THE ORIGINAL TISSUE. SOMETHING WE SHOULD DO. >> SO, IF IT'S COLD LIKE MOST OF THESE T CELLS PROBABLY WILL NOT GET THERE. >> (INAUDIBLE). >> THE IDEA OF THE COLD TUMORS, REFERENCES, LOWER MUTATIONAL BURDEN (INAUDIBLE). >> WHAT WAS THE QUESTION? >> NEW IMMUNE CELLS PRESENT IN PRIMARY DISEASE, THE CHALLENGE IS (INAUDIBLE). >> YEAH, YOU'RE RELYING ON THE IDEA HIS OWN IMMUNE SYSTEM WOULD HAVE BEEN ABLE TO MOUNT SUFFICIENT RESPONSE AND GENERATED SPECIFIC T CELLS THAT WOULD ATTACK THAT TUMOR ESSENTIALLY. SO WE CLEARLY USING ADOPTED CELLULAR APPROACH, YOUR BODY IS NOT ABLE, BUT T CELLS THEY CAN TRACK TO IF ARE ACTIVATED AND EXPANDED. >> YOU'RE TALKING ABOUT T REGs? >> NICK HAS LOOKED AT EPENDYMOMAS IN GENERAL AT CELLULAR POPULATIONS, THIS IS A SAFETY STUDY, SO WE'RE GATHERING THAT TISSUE AND WE WILL DO THOSE ANALYSES OF COURSE AT THE END. BUT, NICKF YOU WANT TO TALK ABOUT IMMUNOPHENOTYPE. >> MICROPHONE. >> PRELIMINARY DATA, I WOULDN'T ACTUALLY BANK ON IT WITHOUT SOME MORE WORK, YOU ACTUALLY -- THE LESIONS ARE IMMUNOLOGICALLY COLDER WHEN THEY ARE METASTATIC LIKE THIS. SO THE PRIMARY LESIONS CAN HAVE QUITE EXTENSIVE T CELL AND OTHER INFILTRATES AND THINGS, BUT THE METS OFTEN DON'T. AND I DON'T REALLY UNDERSTAND THE REASON FOR THAT. BUT THAT APPEARS TO BE THE CASE. >> SO, MARK, DO YOU WANT TO MAKE A COMMENT HOW YOU WOULD HAVE MANAGED THIS PATIENT AT RECURRENCE? >> HOW OLD WAS THE KID? >> TWO. AND THREE WHEN HE RECURRED. >> WE WOULD BE PRESENTING OUR DATA THIS AFTERNOON, SO WE'VE DONE A STUDY IN INFANT LESS THAN THREE YEARS OF AGE, SUPERTENTORIAL, ALL GOT UPFRONT CHEMOTHERAPY FOR FOUR COURSES AND FOCAL RADIATION THERAPY. THAT'S THE WAY WE MANAGED THEM. THERE WERE A COUPLE WE TOOK BACK FOR SECOND RESECTION, AND THEN THERE WAS AN INFANT WHO FINISHED A CHEMO COMPONENT AT ONE YEAR OF AGE, WHICH PARENTS REFUSED RADIATION THERAPY, I THINK THERE'S A SPECTRUM OF DISEASE IN THIS AGE GROUP, AND JUST LIKE WAS DISCUSSED BRIEFLY YESTERDAY, DR. CHRISTIAN'S DATA RETROSPECTIVELY SHOWED RELAYS DID POORLY, IN PROSPECTIVE DATA I THINK THAT'S NOT TRUE. >> ANY FINAL COMMENTS? IF NOT I REALLY WANT TO THANK OUR THREE PRESENTERS FOR YOUR EXCELLENT JOB. [APPLAUSE] AND FOR OUR FANTASTIC PANEL FOR WHAT WAS A GREAT DISCUSSION.