>> GOOD AFTERNOON AND WELCOME TO TODAY'S GRAND ROUNDS. ON OUR SPEAKERS ARE FROM THE THYROID ONCOLOGY PROGRAM AND THE MEDICAL INSTITUTE'S ONCOLOGY BRANCH AND THEY'LL ADDRESS WHAT'S NEW IN THYROID CANCER. SPEAKING FIRST AND DR. SAMUEL WELLS WHO IS A SENIOR CLINICIAN AND THYROID ONCOLOGY PROGRAM DIRECTOR AND DR. AN AFTERNOON GRAMZA WILL WILL FOLLOW. DR. WELL SYSTEM A GRADUATE OF THE SCHOOL OF MEDICINE AND RECEIVED TRAINING AT THE JOHNS COP KIN UNIVERSITY HOSPITAL AND ALSO COMPLETED A SURGICAL RESIDENCY AT THE DUKE MEDICAL CENTER. FROM 1981 THROUGH 1998, HE CHAIRED THE DEPARTMENT OF SURGERY AT THE WASHINGTON SCHOOL OF MEDICINE AND HE WAS THE PRINCIPLE FOUNDER OF THE AMERICAN COLLEGE OF SURGEON'S ONCOLOGY GROUP AND SERVED AS THE FIRST CHAIR OF 1997 UNTIL 2005. DR. WELLS SPENT SIX YEARS IN BASIC LABORATORY AND INVESTIGATION SURGERY BRANCH, FIRST THE CLINICAL ASSOCIATE AND LATER AS SENIOR INVESTIGATOR AND AT THE INSTITUTE FOR TUMOR BIOLOGY AT THE CAROL LYNN SKA INSTITUTE IN STOCK HOME. HE'S BEEN IN HIS CURRENT POSITION SINCE NCI SINCE 2009 AND DR. WELL SYSTEM A FELLOW OF THE AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, AND THE AMERICAN COLLEGE OF SURGEONS. HIS MEMBERSHIPS INCLUDE THE AMERICANS SOCIETY FOR CLINICAL INVESTIGATION IF THE ASSOCIATION OF AMERICAN PHYSICIANS. HE'S ALSO THE RECIPIENT OF THE AMERICAN RADIANT SOCIETY JANE WAY METAL AND THE AMERICAN SURGICAL ASSOCIATION FOR SCIENTIFIC ACHIEVEMENT. HIS MAJOR RESEARCH INTEREST INCLUDE THE STUDY OF THE MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES AND THE DEVELOPMENT OF TARGETED THERAPY FIST FOR THYROID CARCINOMA. HIS GROUP HAS HAD A LONG INTEREST IN BASIC AND CLINICAL INTEREST RELATED TO MADULARY THYROID CANCER. DR. GRAMZA WHO FOLLOWS IS A GRADUATE OF THE OHIO STATE UNIVERSITY COLLEGE OF MEDICINE. HE COMPLETED RESIDENCY AT THE UNIVERSITY OF NEW MEXICO ISUENTS ON TO COMPLETE A FELLOWSHIP IN HOSPICE AND PALLIATIVE CARE, PALLIATIVE MEDICINE THERE AND IN HEMATOLOGY AND MEDICAL ONCOLOGY AT THE OR HEALTH AND SCIENCE UNIVERSITY. DR. GRAMZA WHO HAS BEEN AT NCI SENT THE 2010 AT THE AMERICAN THYROID ASSOCIATION AND THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY. RESEARCH INTERESTS FOCUS ON ENDOCRINE ONCOLOGY, PARTICULARLY STUDIES OF MULTIPLE ENDOCRINE NEOPLAYSIA AND MEN TYPE TWO SYNDROMES. RESEARCH ALSO INCLUDES CLINICAL TRIALS DESIGNED TO EVALUATE THE EFFICACY OF MOLECULAR TARGETED THERAPEUTICS TO TREAT PATIENTS WITH ADVANCED THYROID CANCER. AND NOW I WELCOME DR. WELLS, THANK YOU. >> THANK YOU VERY MUCH FOR THE NICE INTRODUCTION. THIS IS NOT A VERY TOPICAL TOPIC, YOU MIGHT SAY BECAUSE THE CANCER IS NOT THOUGHT TO BE A MAJOR PUBLIC HEALTH PROBLEM. THAT IN FACT IS NOT THE CASE. AS I WAS SHOWING A MOMENT AND THIS DISEASE ATTRACTED A GREAT DEAL OF INTEREST OVER THE LAST FEW YEARS FOR TWO REASONS. THE FIRST IS THAT THE INCIDENCE OF THIS DISEASE IS INCREASING MARKEDLY AND THE REASONS FOR IT IS CLEAR WILL ALL COME THROUGH IN A MOMENT. THE PURPOSE OF THIS TALK IS TO FIRST MOVE ON PROVIDE AN OVERVIEW OF THE EPIDEMIOLOGY OF THYROID CANCER, TALK ABOUT THE GENETIC MUTATIONS CHROMOSOMAL TRANSLOCATIONS THAT CAUSE THE MORE COMMON TYPES OF THYROID CANCER AND LAST REVIEW THE CLINICAL TRIALS THAT HAVE REALLY BEEN VERY RECENT, ALL OCCURS IN THE LAST FIVE TO SIX YEARS. THE INCIDENCE OF THE INCREASING RATE OF CANCER AS I SAID IS NOT KNOWN, IS NOT JUST AT THE INCIDENT IS INCREASING BUT THE INCIDENCE OF CANCER DEATHS IS INCREASING, SECONDARY ONLY TO LIVER AND BIODUCTS. IT'LL BE MORE THAN 48,000 NEW CASES OF THYROID CANCER AND 1740 THYROID CANCER DEATHS. THESE SEER DATA FROM MY TEAMS, 95-2004 SHOWING THE INCREASED INCIDENCE AND THE INCREASE TRENDS IN CANCER DEATHS. IT IS ESPECIALLY PROBLEMATIC IN OLDER PATIENTS. OVER 65 YEARS OF AGE WHERE THE INCIDENCE, THE TREND IN CANCER DEATHS IS MARKEDLY INCREASING. THIS ORIGINALLY WAS THOUGHT TO BE DUE TO THE FACT THAT THERE WAS INCREASED SCREENING FOR THYROID SCANNER, MORE SCANS SO THE INITIAL DIAGNOSIS OF THYROID CANCER RELATED PRIMARILY TO THE SMALLER TUMORS. IN FACT, THAT'S PARTLY CORRECT, BUT THE OTHER REASONS AS WELL. THIS DISEASE OCCURS THREE TIMES MORE COMMONLY IN WOMEN COMPARED TO MEN, THE REASONS FOR THIS, ARE NOT ENTIRELY CLEAR, BUT IF THE RATE RATE CONTINUES TO INCREASE LIKE THIS, IT'S GOING TO BE A MAJOR PUBLIC HEALTH PROBLEM AND I THINK THE REASON IS NOT ATTRACTED A GREAT DEAL OF MORE INTEREST AS I'LL COME TO IN A MOMENT. IT'S NOT A HIGHLY LETHAL MALIGNANCY. THERE WERE THREE PAPERS THAT REALLY ADDRESSED THE CAUSES FOR THE INCREASED INCIDENCE AND ONE THAT ATTRACTED THE MOST ATTENTION FIRST IS ONE BY DAVEYS AND WELNCH PUBLISH INDEED JMA WHERE THEY DID THIS IT TOTAL TO INCREASED SCREENING AND SURVEILLANCE OF PATIENTS PRESENTING WITH THYROID NODULES, MOST OF THE INCREASE IS CAUSED BY CARCINOMA AND MOST COMMON TYPE AS I'LL COME TO IN A MOMENT. THIS HAS CAUSED A RELATIVE DECREASE IN THE INSTANCE OF OTHER THREE TYPES OF CARCINOMA. THEY WERE TWO SUBSEQUENT PAPERS, THAT ADDRESSED THE ISSUE OF INCIDENCE ALSO AND IT BECAME CLEAR, THERE'S NOT ONLY INCREASED SCREENING BECAUSE ALL STAGES OF OF THYROIDICANCIER ARE INCREASING, SO THE PICTURE IS STILL NOT ENTIRELY CLEAR. PAP ILLEGALSARYS BY FAR IS THE MOST COMMON TYPE, THOUGHT ABOUT FOLLICULAR MADULARY ANAPLASTIC. 10 YEARS AGO IT ACCOUNTED FOR TYPH OR 10% OF THYROID CANCERS BUT AS I MENTIONED THEY'VE BEEN REDUCED BECAUSE OF THE PREDOMINANCE OF PAP ILLEGALSARY CARCINOMA. THE DIFFERENTIATED THYROID CARCINOMAS ALL ARISE FROM THE FOLLICULAR CELLS. THERE ARE TWO CELL LINEAGES IN THE THYROID GLAND, THE FOLLICULAR CELL WHICH IS GIVE RISE TO THE PAP ILLEGALSARY FOLLICULAR AND A PLASTIC CARCINOMA COMPLEX AND THE NEUROENDOCRINE C-CELLS THAT GIVE RISE TO THE THYROID CARCINOMA BUT TRUSTEES THE FOLLICULAR CELL OR DERIVED FOLLICULAR TYPES, FOLLICULAR ADENOMAS AND THEN THE POINT OF DIFFERENTIATED IN ANAPLASTIC CARCINOMAS. BECAUSE THE CARCINOMA IS THE MOST COMMON THE DISEASE HASN'T GOTTEN A VERY BAD REPUTATION AS FAR AS BEING A MALIGNANCY. 95% OF THE PATIENTS WHO HAVE PIP ILLEGALSAR SCHECARCINOMA ARE LIVE WITH NO EVIDENCE OF DISEASE. SOMEWHAT LESS THE CARCINOMA BUT NO PATIENTS WITH THE CARCINOMA LIVE FIVE YEARS AFTER THE DIAGNOSIS, MEDIAN SURVIVAL IS ACTUALLY SIX MONTHS. IT'S REMARKABLE DIFFERENCE IN BIOLOGIC BEHAVIOR, THE SPANS OF THE CELLS FROM THE NOT SO BAD FOLLICULAR TUMORS TO THE HIGHLY LETHAL ANAPLASTIC CARCINOMAS. PAP ILLEGALSARY CARCINOMAS ARE NOT ONLY THE MOST--THEY'RE THE MOST COMMON MALIGNANCY AND THEY'RE CAUSED BY MUTATIONS, MOST COMMONLY IN B-RAUGHT, THIS IS THE B600 E MUTATION, THE SAME THAT OCCURS IN THE MA LIGNANOG AND IN AKA AND REARRANGEMENTS OCCUR IN LESS THAN FIVE%. 30% OF PATIENTS HAVE EXPOSURE TO IONIZING RADIATION WHICH CAUSES CHROMOSOMAL ARRANGEMENTS AND A RETINAL LOCATION PTC TRANSLOCATION WHERE RETINAL LOCATION IS NOT ACTUALLY MUTATED BUT THERE'S A HYBRID ONCA GENE CREATED WHERE THE PROMOTER DRIVES RETINAL LOCATION TO CAUSE A--RET TO CAUSE FOLLICULAR CARC NOME A. THIS BECAME EVIDENT OF THE CHILDREN IN THE CHERNOBYL ACCIDENT AS I'LL COME TO IN A MOMENT. SO THE B-RATH MUTATION ACCOUNTS FOR 40 TO 45% OF THE TUMORS. THESE TUMORS ACT WORSE THAN THOSE WHO DON'T HAVE BRAUGHT MUTATIONS THEY HAVE THYROIDAL EXTENSION, THEY HAVE A HIGHER TUMOR STAGE AND PRECEPTATION, HIGHER RATE OF TUMOR RECURRENCE AND A PROPENSITY FOR D-DEVELOPMENTAL ENDOCRINOLOGY REBTIATION, IF YOU LOOK AT THE CARCINOMAS, IT'S ABOUT 15 OR 20% OF THEM HAVE B-RATH MUTATIONS AND IF YOU DON'T CARE FOR THAT CARCINOMA THESE TUMORS ALMOST ALWAYS YOU'LL FIND SMALL SECTIONS OF PAP ILLEGALSARY CARCINOMA. THE RED PDC ABOUT 10 OR 20%, CLASSIC PAP ILLEGALSARY TYPE, YOUNGER AGE OF PRESENTATION AS I SAID BEFORE, ASSOCIATE WIDE RADIATION EXPOSURE AND THEIR LOWER STAGE OF PRESENTATION. RASE MODEL MUTATIONS OCCUR IN ABOUT 10 TO 20% CLASSICALLY IN THE FOCUSED ON LAKEULAR VARIANT OF PAP ILLEGALSARY CANCER, MORE FREQUENTLY INCAPUE SATED LESS OFTEN LYMPHNODE METASTASIS AND MORE FREQUENT DISTANT METASTASIS AND THERE'S GENOTYPE, PHENOTYPE CORRELATION HERE, NOT MARKED PERHAPS MORE SO FOR THE RET PTC TRANSLOCATIONS AS I'LL COME IN THIS A MOMENT. SO B-RATH MUTATIONS CONSIDERED IN CARCINOMA AND FULLY DIFFERENTIATED AND ANAPLASTIC CARC NOME AS, BUT DID NOT OCCUR IN OTHER TUMORS, THESE ARE MUTUALLY EXCLUSIVE MUTATIONS, WE DID NOT SEE THE B-RATH MUTATIONS AND THE MUTITATIONS OF THE TUMOR AND ABOUT SEVEN% WILL HAVE ONE OF THESE TYPES OF CHROMOSOMAL ABNORMALITIES. ALMOST 25 YEARS AGO, THERE WAS AN ACCIDENT IN CHERNOBYL ALMOST A HUNDRED KILOMETERS NORTH OF KIEV THAT CAUSED AN EXTREME RELEASE IN RADIATION EXPOSURE INTO THE ATMOSPHERE, I-131 DOSE OF TWO TIMES 10 TO THE 18 BECKA RELLS. IT WAS RAIN AND THE WIND WAS SHIFTING AND THE GROUND WAS HEAVILY DRENCHED WITH I131. AT FIRST ALL THE ATTENTION WAS FOCUSED ON ON THE INITIAL EVENT AND THE WORKERS WHO WERE IN THE PLANT AT THE TIME THAT UNIT FOUR EXPLODED BUT WITHIN FIVE YEARS IT BECAME EVIDENT THERE WAS AN INCREASED EVIDENCE OF PAP ILLEGALSARY CARCINOMA OCCUR NOTHING CHILDREN WHERE BEFORE, THERE HAD BEEN ONE PER ONE MILLION AS FAR AS THE INCIDENCE. IT INCREASED 30 FOLD WITHIN 10 YEARS. AND THESE CHILDREN PET TRANSLOCATION WHERE THE BLUE TO THE RIGHT SHOWS THE TYROSEEN KINASE PORTION AND TO THE LEFT IS A SEGMENT OF EITHER INTERCHROMOSOMAL LANES LO LOCATION OCCURS IN PTC ONE AND THREE OR EXTRA CHROMOSOME TRANSLOCATION WHICH OCCURS IN MOST OF THE REST AND AGAIN THIS IS A HYBRID ONCA GENE WHERE RET IS ACTUALLY NOT MUTATED BUT IS DRIVEN BY A PROMOTER WHICH IS ABNORMALLY JUXTAPOSED ADJACENT TO RET. PTC THREE AND ONE ARE THE MOST COMMON TYPES OF ARRANGEMENTS THAT OCCUR IN THE CHERNOBYL ACCIDENT, CHILDREN, RPTC THREE IS ASSOCIATE WIDE A SOLID TYPE HISTOPATHOLOGY AND IT'S NOW CLEARLY UNDERSTOOD, THIS TYPE OF RET TRANSLOCATION OCCURS IN ADULTS WHO RECEIVED RADIATION AS CHILDREN FOR EITHER ENLARGED THYMUS GLAND IN CROUP OR A 10IA CAPITUS AND THE IT'S A SIMILAR TYPE OF DERANGEMENT, NOT AS COMMON AS OCCUR IN THE CHILDREN. THESE TUMORS APPEAR HIGHLY VIRULENT, THEY WERE ASSOCIATED WITH THE METASTASIS, AND WITH THE ORDERLY EXTENSIONS BUT THEY WERE NOT HIGHLY LETHAL IN MOST OF THE CHILDREN BUT DID ABOUT FOLLOWING TOTAL THYROIDECTOMY. I SHOW THIS PICTURE OF ELAINE RON WHO WAS FORMERLY THE HEAD OF THE RADIATION EPIDEMIOLOGY BRANCH IN THE DIVISION OF CANCER, EPIDEMIOLOGY AND GENETICS, HE PASSED AWAY ABOUT SIX MONTHS AGO, HE HAD AN ENNORMOUS IMPACTS OF THE THOI ROADWAY GLAND. SHE WAS INVOLVED IN THE CHERNOBYL INCIDENT AND MANY OTHER ASPECTS AND I SHOW THIS TO GIVE TRIBUTE TO HER FOR THE SUBSTANTIAL BODY OF WORK SHE DID RELATED TO THIS FIELD. FOLLICULAR AUTHORITY CARCINOMA IS ASSOCIATING WITH PAX EIGHT, PPR GAMMA ONE FUSION ORCHGA GENES, IT OCCURS IN ABOUT 62% OF CASES. THIS IS THE RIDGEIT DESCRIPTION BY TODD CONTROL WHO IS AT THE MASSACHUSETTS GENERAL HOSPITAL, HE'S NOW AT EMORY AND OTHER INVESTIGATORS FOUND THIS TO BE IN THE SAME RANGE BUT PERHAPS A SOMEWHAT LESS FREQUENT. THIS ALSO OCCURS, THIS ARRANGEMENT FOR THE FOLLICULAR AUTHORITIES, ADENOMAS, BUT NOT IN PAP ILLEGALSARY CARC NOME AS OR ANAPLASTIC THYROID CARCINOMAS. AN UNCOMMON BUT PERHAPS THE MOST INTEREST TO OUR GROUP AS BEEN MADULARY THYROID CARCINOMA FOR SEVERAL REASONS. ONE IS IT PRESENTS IN EITHER A SPORADIC PATTERN, 75% OF THE TIME OR IT OCCURS IN THE FAMILIARIAL PATTERN EITHER AS MM. E. N. TWO A OR M. E. N. TWO-C, IT'S ALWAYS BILATERAL WHEN IT OCCURS IN A PAT EXPERN IT'S INHERITED AS AN AUTOSOMAL DOMINANT TRAIT SO HALF THE CHILDREN ARE FROM A PARENT THAT WILL CONTRACT THE DISEASE. IT'S ALSO ASSOCIATE WIDE THE CRYOSIGNIFY TELOMERAS, ABOUT 50% OF CASES IN TWOA AND TWO B AND THE PATIENTS HAVE A VERY CHARACTERISTIC PHYSICAL APPEARANCE. CAN YOU RECOGNIZE THEM IF YOU SEE THEM ON THE STREET, THEY DO NOT HAVE PARATHORRA DISEASE, THEY DO HAVE PARATHORRA DISEASE, SO THE CARCINOMA IS A BILATERAL FAMILIESIAL DISEASE WITH NO OTHER ENDOCRINE OPERATING GLOBALLYATHYS AND DEPENDING ON THE STUDY IN WHICH THIS OCCURS, IT'S EITHER NOT SO BAD, AS IF FAMILIESIAL CARCINOMA OR AS HIGHLY AGGRESSIVE, AS M. E. N. TWO B, AND THESE TUMORS ARE CAPRICIOUS, DEPENDING ON WHERE THE MUTATION OCCURS AND THE ONCA GENE THEY'RE EITHER AGGRESSIVE OR THEY'RE NOT HIGHLY AGGRESSIVE. THIS IS THE GENE THAT'S SIMILAR TO TWO TYPES OF THE CARCINOMA, PRIMARILY THE MADULARY CARCINOMA WHERE ALL PATIENTS WITH THE HER HEREDITARY TYPE WILL HAVE A GERM LINE MUTATION IN THE ORCHA GENE, MOST PATIENTS WITHIN THE NTWOA HAVE YOU HADITATION IN ONE OF THREES FIVE CODONS AND THE EXTERNAL LIGAND SITE, MOST BUT NOT ALL PATIENTS WITH FAMILIARIAL VAGINARY CARCINOMA HAD MUTATIONS OF THESE TWO CODON SITES AND VIRTUALLY ALL PATIENTS DURING THE 95%, WITHIN NA-TWO B HAVE MUTATION AT CODON 19 THIS IS SUBSTITUTION, THESE ARE ALL POINT MUTATIONS. IT OOSKTS THE CONTOUR, THE SUBSTRATE BINDING POCKET AND THE SUBSEQUENT PHOSPHORYLATION OF THE SUBSTRATE OF THIS ATP SITE. THIS ONCA GENE ALSO IS ASSOCIATED WITH HEARSE SPRUNG'S DISEASE, THIS IS SHOWN BY THE GREENE TRIANGLES THROUGHOUT THE GENE, ABOUT 50% OF CASES FROM THE DISEASE HAVE RED CODON MUTATIONS AND ABOUT 25% ARE SPORADIC DISEASE. HERB SPRUNG'S DISEASE IS WHERE THEY HAVE LOSS OF GANGLION CELLS IN THE LARGE DISTAL BOWEL. IT CAN BE A PEDIATRIC EMERGENCY IF THEY'RE NOT TREATED SURGICALLY IN TIME. IN A SIMPLISTIC FASHION, THESE MUTATIONS THAT OCCURRED WITH HERB MAN'S DISEASE CAN BE CONSIDERED LOSS OF FUNCTION MUTATIONS, WHEREAS IN MUTATIONS THAT OCCUR WITH MADULARY CARCINOMA SHOULD BE CONSIDERED GAIN OF FUNCTION MUTATIONS. AND CHILDREN WITH FAMILIARIAL MADULARY CARCINOMA, WHETHER IT'S ME. N. TWO A OR TC. CAN YOU MAKE THE DPTIONIS VERY EARLY, PREALIEN IN THE FIRST DAY OF LIFE, THEY HAVE THE MUTATION IN THE WHITE BLOOD CELLS. ABOUT 75% OF THE TIME OF THE MUTATION IS AFFECT BIGHTED A RESTRICTED ENDONUCLEACE SITE WHICH WILL CUT THE DNA INTO TWOBIANS. THESE ORANGE INDIVIDUAL SHALL ARE ALL DIAGNOSED, THESE FIVE CHILDREN, ALL THE PARENTS WITH AN AFFECTED STATUS HAVE TWO BANDS. AND OF THESE FIVE CHILDREN, OF THESE TWO, YOU TELL THIS CHILD AND THEIR PARENTS IF THEY WILL NEVER INHERET THE DISEASE, NOR WILL THE DESCEND ANTS NEED TO BE TESTED AGAIN, SAME FOR THIS YOUNGSTER HERE, THESE TWO BROTHERS. THESE CHILDREN WHO HAVE INHERITED A MUTATED ALLELE ARE GOING TO DEVELOP THYROID CARCINOMA AT SOME TIME AND THE PROPHYLACTIC THYROIDECTOMY AND THIS HAS BECOME THE WAY TO TREAT THE PATIENTS WITH THE CARCINOMA. YOU TAKE THE THYROID GLAND OUT PARPRIOR TO THE TIME THEY DEVELOP THE MALIGNANCY OR THE GLAND OF THE STAGE BEFORE IT'S METASTASIZED. AND WE STUDIED 50 CONSECUTIVE CHILDREN WHO HAD A PROVE LACTIC ACIDOSEISICT THYROIDECTOMY AND 88% OF THESE CHILDREN WERE CURED. BY CURED I MEAN, FIVE YEARS EVALUATION THEY HAD NO EVIDENCE OF DISEASE AND THE MOST CRITICAL DETERMINANT OF THAT IS WHETHER THE CALCTONEIN IS ELEVATED. CALCTONEIN IS A POLYPEPTIDE HORMONE SECRETED BY C-CELLS, IT'S SPECIFIC FOR MADULARY CORS NO, MA'AMA IF YOU GIVE PATIENTS CALCIUM AND PENTAGHAST RIN. THE PROVOCATIVE AGENTS STIMULATE RELEASE. THESE CHILDREN, THE 88% ALL H. I.T A TOTALLY FLAT LINE. THEY HAD NO INCREASE OVER BASAL LEVELS, WHEREAS THE CHILDREN SHOWN HERE DID HAVE AN INCREASE, EVEN THE MINIMAL INCREASE, THIS HAS BEEN THE NORMAL RAIMPLEG OF CALCTONE AND IF THEY HAD AN INCREASE OVER BASAL, THEY'VE GOT C-CELLS REMAINING AND THEY HAVE RESIDUAL MADULARY CARCINOMA. THIS IS A WONDERFUL WAY TO TREAT CARCINOMA BECAUSE IT'S NOT LIKE CHEMO THERAPY OR MOLECULAR TARGETED THERAPEUTICS YOU HEAR ABOUT IN A MOMENT. THERE ARE NO CELLS THAT ARE TREATED THIS WAY AND CURED. THEY DON'T DEVELOP AMPPLIFICATIONS OR D-MUTATIONS IN THE ACTIVATION SITE UNFORT MATILY THIS OPPORTUNITY DOESN'T COME ALONG WITH VERY MANY SOLID TUMORS AND INDEED, EVEN IN PATIENTS WITH AMEL YOID CARCINOMA PRESENT WITH A THYROID NODULE. ANAPLASTIC CARCINOMA, ORIGINATES FROM DIFFERENTIATED CARCINOMAS, THE HIGHLY MUTATED P53 BETA KACCT TINEIN AND B-RAUGHT MUTATIONS AGAIN THESE ARE HIGHLY LETHAL, THEY HAVE MARKED INBALLANCE AND CHROMOSOME AMPLIFICATION IS DELETION, ALMOST EVERY CHROME SO STUDIES OF MULTIPLE ENDOCRINE. SO IT'S A VERY DIFFERENT TUMOR FROM THE OTHER HISTOLOGIC TYPES. THERE IS A BRIGHT LIGHT ON THE HORIZON WITH ANAPLASTIC THYROID CARCINOMA, THERE'S BEEN TWO STUDIES, THIS FROM THE MAYO CLINIC AND WE'RE PATIENTS TREAT WIDE ADJUVANT CHEMEE THERAPY, SIS PLATIN PRIMEAR ILLEGALS SCHERADIO SENSITIZING CHEMO THERAPY AFTER FRACTIONATED RADIATION, WHICH GAVE A PROLONGED SURVIVAL COMPARED TO HISTORIC CONTROL TO THE MAYO CLINIC DOES NOT GET BETTER RANDOMIZED STUDY. THERE WAS ANOTHER STUDY DONE BY ANOTHER INSTITUTION WITH A SIMILAR RESULTS SO PERHAPS VERY AGGRESSIVE THERAPY IN THESE PATIENTS WILL CHANGE THE OUTCOME BUT UNTIL THEN IT'S A VERY AGGRESSIVE TUMOR. NOW TILL ABOUT EIGHT YEARS AGO, THIS IS WHERE THYROID;LyPk CANCER STOOD, HERE'S A PATIENT SITTING IN THE DOCTOR'S OFFICE, THERE'S NO CURE, NOT EVEN A RACE FOR A CURE. THE ONLY TREATMENT FOR PATIENT WHO IS DEVELOPED ADVANCED DISEASE OTHER THAN EXTERNAL RADIO THERAPY FOR FOLK AT LESIONS, WAS CHEMO THERAPY AND THE ONLY DRUG APPROVED BY THE FDA TO TREAT THESE PATIENTS WAS DOXORUBICIN. I WON'T SHOW DATA FOR CHEMO THERAPY TRIALS BECAUSE ALMOST ALL ARE CHARACTERIZED BY RATIO RESPONSE RATES AND VERY LOW RESPONSE RATES AND IT IT WAS CLEAR THESE PATIENTS THEY DEVELOP METASTATIC DISEASE DEVELOP A VERY DIFFICULT COURSE. THIS SLIDE SHOWS THE SIBLING PATHWAYS THAT ARE ACTIVATED IN PATIENTS WITH THYROID CARCINOMA, ALMOST ALL THE HISTOLOGIC TYPES, COMES DOWN THE MAP KINASE PATHWAY, INVOLVING GRASS, MATH AND ERK, AND AKT, mTOR MATH WAY. THIS COULD BE GREATLY AMPLIFIED BUT IN AICISM POLITIC WAY, THE MOST THAT AFFECT AND CAUSE THESE CARCINOMAS OCCUR IN THIS COMPLEX. THESE DATA THAT SHOW THE VARIOUS HISTOLOGIC TYPES OF THYROID CARCINOMA AND THE ASSOCIATED MOLECULAR DERANGEMENTS THAT OCCUR WITH THEM, STARTING WITH THE FOLLICULAR CELL AND FOLLICULAR ADENOMAS, WHAT ROLE PACKS THE ATP R GAMMA ONE PLAYS IS NOT ENTIRELY CLEAR IS CERTAINLY MUTATED AND CERTAIN PORTION OF THESE PATIENTS. ALMOST CERTAINLY THIS MUTATION AND RAS ACCOUNT FOR FOLLICULAR ADENOMA AND THEY CERTAINLY ACCOUNT FOR FOLLICULAR CARCINOMAS AS I MENTIONED EARLIER. THE RED PTC RED RARADIATION EXPOSURE RASE MODEL BRACKET, LEAD TO PAP ILLEGALSARY CARCINOMA AND THE POORLY DIFREPRESENTIATED NANO PLASTIC TYPES ARE DERIVED DOWN THE SAME PATHWAY FROM FOLLICULAR CELLS. THIS SHOWS THE VARIOUS TYPES OF MUTATIONS, MOST OF WHICH I'VE MENTIONED PREVIOUSLY THAT OCCUR IN THE VERY HISTOLOGIC TYPES AND I WOULD AGAINST THE CARCINOMA HIGH INCIDENCE OF RAS, BRATH, AND P53 AND THE PITHREE CAIN ACE PATHWAY. THE CARCINOMA IS A STRAIGHT SHOT FROM THE C-CELL TO THE MADULARY CARCINOMA. MAKING THE CARCINOMA ISN'T THYROID CANCERS, THESE CELLS COME FROM THE NEURAL CREST AND BIRDS AND FISHES THEY'RE A SEPARATE STRUCTURE CALMED THE BRACHIAL BODY AND VERY EARLY THE LIFE, WE SELL THE STREAM, THEY POPULATE THE PILOT PROJECT TUEITARY AND THE COMPLEX, AND THEY BECOME ENTRAPPED IN THE LATERAL COMPLEX AS IT CLOSES DURING EMBRYO GENESIS BUT BECAUSE IT OCCURS IN THE THYROID GLAND, THEY'RE CALLED THYROID CARCINOMAS. I WANT TO MOVE NOW TO A BRIEF DESCRIPTION OF THE PRECLINICAL WORK THAT LED TO TWO OF THE CLINICAL TRIALS THAT WERE DONE IN MADULARY CARCINOMA AND IT INVOLVED THIS COMPOUND OF ZD6474, WHICH SELECT SELECTIVELY TARGETS VGFR AND RETINAL LOCATION, THE STRUCTURE, OF THIS COMPOUND, IT'S A POTENT VEG FRTWO AND RET INHIBITOR AND ORIGINALLY THE WORK THAT WAS DONE IN THE LABORATORY, BY FRANCESCA CARLA MAG NO AND WE ACTUALLY HAVE TWO POST DOCTORAL FELLOWS HERE FROM DR. SAN TORO'S LABORATORY AND AND THEN A TAM BA RIN O WHO ARE BOTH WORKING HERE ON THYROID CARCINOMA. SO SHOWING THE VARIOUS MUTATIONS THAT IF YOU TAKE CD674, THERE'S A DECREASING EXPRESSION OF THE TUMORS. YOU INCREASE THE DOSE OF ZD6474, THIS WOULD BE EFFECTIVE THERAPEUTICALLY IN PATIENTS WHO HAD MADULARY CARCINOMA IN ADVANCE STAGE AND IF YOU TRICK MICE WHO HAVE A RET PTC TRANSLOCATION WHERE RET IS TREATED AND YOU TREAT THEM AND THE VEHICLES GROW @ SAME RATE, THIS IS ZD6474, FILL GRAM A MOUSE A DAY, THIS IS A VEHICLE NOT RELATEDDED TO THE THERAPEUTIC CONTRACT IS POINT FOUR MILL UPON GRAMS--.4-MILLIGRAMS GIVE YOU A SIMILAR TYPE, INHIBITIONS TO CONTROL NOT THAT MUCH DIFFERENCE BUT A STRIKING DIFFERENCE WITH ONE MICROGRAM. IF YOU LOOK AT THE MICE, NUDE MICE WITH THE TUMORS THESE ARE UNTREATED, THESE ARE TREATED, AGAIN, THE INDEX, THIS MIGHT HAVE THERAPEUTIC EFFICACY IN THE CLINIC. THE OTHER LINE OF EVIDENCE THAT THIS WOULD WORK CAME FROM THE DROSOPHILA MODEL, THESE ARE DATA FROM ROSS KEYINGIN AND MOUNT SINAI NEW YORK AND THIS DROSOPHILA RETINA HAS 750 UNIT EYES, EACH ONE MADE UP OF PRECISELY 14 CELLS, EIGHT OF WHICH ARE PHOTORECEPTOR CELLS, AND THIS GEODESICC TYPE OF PATTERN AS UNDER THE CONTROL OF THE GMR PROMOTER AND IF ONE DOESN'T HAVE THE MUTE O GENESIS AND PLACES IN RET MUTATED ALLELE, AND ALLOWS YOU TO BE EXPRESSED IN THE HIGH, ONE GETS THIS APPEARANCE, NOT THE WILD-TYPE GOING, BUT THIS VERY NEURAL DERANGED STRUCTURE, IF YOU TREAT THE FLY LARVA WITH CD6474, .2, MILLI MOLAR CORRECTS IT. IT'S A WONDERFUL ASSAY FOR WHETHER OR NOT THIS HAS ANY EFFECT ON THE MUTATION THAT OCCURS THAT'S REVERTED TOTALLY FROM THIS PATTERN TO A WHILED TYPE PATTERN WITH TREATMENT. WITH WHICH IS THE SECOND LINE OF EVIDENCE THAT THIS WOULD WORK. NOW I WANT TO TURN NOW TO ANN GRAMZA WHO WILL REVIEW THE CLINICAL TRIAL DATA TO DATE, BOTH WITH DIFFERENTIATED CARCINOMA AND WITH MADULARY CARCINOMA.o[[ >> ALL RIGHT, SO BRIEFLY I'M GOING TO OVERVIEW OR DO A BRIEF OVERVIEW OF THE DIFFERENTIATED THYROID CANCER TRIALS FOLLOWED BY DISCUSSING MOSTLY MADULARY THYROID CANCER AND THEN, AND THEN TO COMPLETE THE TALK, I'LL BRIEFLY DISCUSS THE ONGOING TRIALS HERE IN THE MEDICAL CONICOLOGY BRANCH FOR THYROID CANCER, THIS SLIDE SHOWS THE CURRENT TRIES THAT HAVE BEEN DONE IN THYROID CANCER USING VARIOUS KINASE INHIBITORS, SUCH AS ACSIT NIB, POETIC TOUSES NIB, SER AFNIB, SUNIT NIB AND VAN DETAILS NIB. THEY'RE ALL PHASE TWO TRIALS, THEY ALL HAVE A RELATIVELY SMALL NUMBER OF PATIENTS AND VERY SIMILAR PATIENT RESPONSE RATES ANYWHERE FROM 15% TO 49% DEPENDING ON THE STUDY. WHAT'S BEEN FOUND IS THAT THOUGH THE RESPONSE RATES ARE RELATIVELY LOW, THERE ARE A LARGE PERCENTAGE OF PATIENTS WHO GET CLINICAL BENEFIT FROM THESE DRUGS AND IT'S UNKNOWN WHY THEY WORK. MOST OF THE PATIENT WHO IS DO RESPOND TO SOME DEGREE HAVE STABLE DISEASE RATHER THAN A PARTIAL RESPONSE. IT'S THOUGHT THAT THE MECHANISM OF RESPONSE IS LIKELY RELATED TO THE INHIBITION OF VEG FR BECAUSE HA IS THE KINASE THAT ALL THESE DRUGS DO INHIBIT. SOME OF THEM ALSO WILL INHIBIT THE RET KINASE AS WELL AS OTHER TYROSEEN KINASEIS, BUT UNFORTUNATELY TISSUE STUDIES HAVEN'T BEEN CONDUCTED THAT HAVE BEEN DEFINITIVELY SHOWN THE MECHANISM OF ACTION OF THESE DRUGS. THIS SLIDE AS MULTIPLE WATER FALL PLOTS AND I BASICALLY WANT TO SHOW YOU THAT ALL OF THEM LOOK THE SAME NO MATTER WHAT DRUG IS USED. FOR THOSE OF YOU WHO ARE UNFAMILIAR WITH THE WATER FALL PLOT, HERE YOU CAN SEE, THIS IS ZERO, SO THESE ARE--THIS IS THE BASELINE OF PARENTS AND--PATIENTS AND THE Y-AXIS IS THE MAXIMUM CHANGE IN TARGET LESION SO A PARTIAL RESPONSE IS CONSIDERED A DEE CREASE OF MORE THAN--OF 30% OR MORE AND THEN IN GROWTH IS SHOWN HERE. SO, ACROSS THIS LINE, WE HAVE PATIENTS WHO HAVE PARTIAL RESPONSES AND HERE YOU SEE PATIENT WHO IS ARE CONSIDERED TO HAVE STABLE DISEASE BECAUSE WHILE THEY HAVE SOME DECREASE IN TUMOR MEASUREMENTS, THEY DO NOT MEET THE CRITERIA OF A PARTIAL RESPONSE. AND IT'S FELT THAT THOSE PATIENTS STILL DO ACHIEVE SOME CLINICAL BENEFIT, PARTICULARLY IF THEY HAVE A ROUGH ATOM LONGED PERIOD OF STABLE DISEASE OF SIX MONTHS OR MORE. CURRENTLY, THERE ARE PHASE THREE TRIALS ONGOING WITH SER AFNIB, THIS I BELIEVE JUST COMPLETED ACCRUAL COMPLETING IT TO PLACEBO BUT RESULTS ARE UNAVAILABLE. THERE'S ALWAYS A PHASE THREE TRIAL WITH ANOTHER VEG FR INHICK THOR CALLED E78080 AND THAT IS ACCRUING PATIENTS. SO WHILE WE DO HAVE PROMISING PHASE TWO DATA, THERE'S STILL NO APPROVED THERAPY OTHER THAN DOCKSA RUBE SIN FOR ADVANCED METEDDA STATIC DIFREBTIATED THYROID CANCERS. 2K-678. SO NOW I'LL MOVE TO TO TALK ABOUT THE MADULARY CANCER THYROID TRIALS. SHY FIRST POINT OUT THAT--I SHOULD FIRST POINT OUT THAT VAN DETAILS NIB, THE DRUG THAT DR. WELLS DRIBS THE PRECLINICAL DATA FOR, THIS IS THE DRUG THAT HAS THE MOST CLINICAL DATA IN MADULARY THYROID CANCER INCLUDING THE ONLY PUBLISHED AND PRESENTED PHASE THREE DATA. XL 184 IS RET INHIBITOR AS WELL THAT HAS BEEN STUDIED IN THE PHASE THREE TRIAL, BUT THIS DATA HASN'T BEEN PRESENTED YET. THESE OTHER AGENTS HAVE EFFICACY TO VARYING DEGREES BUT THEY'RE JUST IN PHASE TWO STUDIES. AND AGAIN, YOU CAN SEE ALL OF THESE DRUGS DO INHIBIT THE VEG FR RECEPTOR, WHEREAS ONLY FOUR OF THEM HAVE ACTIVITY AGAINST RET WITH XL 184 AND VAN DETNIB HAVING THE STRONGEST INHIBITORY CONCENTRATIONS. PATE RESPONSE RATES VALID AND RELIABLE SCHETHERE'S SOME PROGRESSION FREE RADICALS SURVIVAL DATA BUT IT'S DIFFICULT TO INTERPRET WITH PHASE TWO STUDIES. AS I'VE MENTIONED BEFORE SOME OF THESE DRUGS INHIBIT OTHER KINASES AS WELL. I DIDN'T INCLUDE THE WATER FALL PLOTS HERE BUT I DID WANT THE TO SHOW YOU SER AFNIB AND MUSEUM TOC NIB DATA. MUTOC NIB DATA IS A WEEK INHIBITOR, VERY FEW PARTIAL RESPONSES WERE SEEN IN THESE PATIENTS WHEREAS XL 184 WHICH IS A MORE POTENT RETINAL INHIBITOR DID HAVE A GOOD NUMBER OF THESE EXPANDED PHASE ONE TRIAL AND SERAFNIB WHILE THE STUDIES ARE FEW, IT DOES APPEAR TO HAVE SOME ACTIVITY IN THIS DISEASE. SO NOW I'LL GO TO TO DISCUSS THE CLINICAL DATA FOR VAN DETNIB OR ZD4674, AND VEG FEGFR INHIBITOR, THE FIRST STUDY WAS BETWEEN NOVEMBER 2004 AND AUGUST OF 2006. THESE PATIENTS ALL HAD HER EDITTERY THYROID CANCER WERE UNRESECTABLE, H. I.T MEASURABLE DISEASE AND LOCALLY ADVANCED OR METASTATIC DISEASE. DRNCHL THEY HAD TO HAVE A CONFIRMED DIAGNOSE OF M. E. N. TWO A, M. E. N. TWO B OR MADULARY CANCER MEANING THEY HAD TO DEMONSTRATE A GERM LINE MUTATION IN THE RET PROTOONCA GENE, GOOD PERFORMANCE STATUS WITH FORMAL ORGAN FUNCTION AND THEY WERE TREAT WIDE VAN DETNIB, 300-MILLIGRAMS DAILY AND DISEASE PROGRESS OR OTHER RITERIUM WAS MET. THE PRIMARY OBJECTIVE IN THIS STUDY WAS OBJECTIVE TUMOR RESPONSE BY RESIST CRITERIA THE DATA CUT OFF FOR THIS STUDY WAS IN FEBRUARY 2008. HERE ARE THE RESULTS IN TABLE FORM. THERE ARE 30 PATIENTS, 20% HAD A CONFIRMED PARTIAL RESPONSE WITH 53% HAVING STABLE DISEASE FOR AT LEAST 24 WEEKS OR SIX MONTHS, I SHOULD POINT OUT THAT FIVE OF THESE PATIENT HIS UNCONFIRMED PARTIAL RESPONSES AND THAT'S BECAUSE CONFIRMED PARTIAL RESPONSE BY RESIST CRITERIA REQUIRES TWO CONSURVEYS CUATIVE CAT SCANS SHOWING A DECREASE BY 30% OR MORE, AND FOUR OF THE FIVE PATIENTS HAD UNCONFIRMED PATE RESPONSES HAD THEIR INITIAL RESPONSE SCAN DONE IMMEDIATELY PRIOR TO DATA CUT OFF. 20% OF PATIENTS HAD STABLE DISEASE FOR MORE THAN EIGHT WEEKS BUT LESS THAN 24 WEEKS. AND ONLY ONE PATIENT HAD PROGRESSIVE DISEASE AS BEST RESIST RESPONSE. ONE WAS UNEVALUATABLE. TUMOR MARKERS CALCTONEIN AND C. E. A. WHICH ARE PRODUCED BY THE C-CELLS IN THIS MALIGNANCY, 74% OF THEM HAD A DECREASE BY 50% OR MORE AND 53% HAD A CC. E. A. DECREASE OF 50% OR MORE. THE MEDIAN DURATION OF RESPONSE WAS 10.2 MONTHS, ANYWHERE FROM TWO TO 17 MONTHS IN ALL PATIENTS. AND THE MEDIAN PROGRESSION FREE SURVIVAL WAS 28 MONTHS. SO THIS LED TO THE LARGER PHASE THREE RANDOMIZED TRIAL, LOOKING AT VAN DETAILS NIB VERSES PLACEBO OH EAND HERE'S THE WATER FALL PLOT SHOW NOTHING YELLOW THE CONFIRMED PARTIAL RESPONDERS AND IN BLUE THE UNCONFIRMED. AS WELL AS CALCTONEIN LEVELS AND DECREASE IN PATIENT WHO IS HAD CONFIRMED PARTIAL RESPONSES, AS WELL AS THE PATIENT OF STABLE DISEASE JUST TO SHOW YOU THAT THERE WAS A SIGNIFICANT DECREASE IN THE CALCTONEIN COMPARED TO PATIENT WHO IS HAD STABLE DISEASE. THIS TABLE IS LOOKING AT THE COMPARISON OF OBJECTIVE RESPONSE WITH THE BEST CALCTONEIN RESPONSE AS WELL AS GERM LINE RAT MUTATION IN PATIENTS WHO HAD TUMOR SHINKAGE OF AT LEAST 20%. HERE ARE THE CONFIRMED PARTIAL RESPONDERS AND AS YOU CAN SEE, THEY HAD A SIGNIFICANT DECREASE IN THE CALCTONEIN LEVEL, AND UNFORTUNATELY, NO CORRELATION WAS FOUND WITH THE RET GERM LINE MUTATION AND RESPONSE. YOU WOULD HOPE THAT WE WOULD SEE THAT TO BE THE CASE. THOSE HAVE BEEN SEEN IN OTHER MALIGNANCIES PARTICULARLY GASTROINTESTINAL STROMAL WHERE THE KINASE INHIBITOR RESPONSE CORRELATES WITH THE MUTATION, BUT THAT HASN'T BEEN SHOWN TO BE THE CASE AS OF YET. >> ADVERSE EVENTS IRRESPECTIVE OF CAUSALITY ARE SHOWN HERE. MOST COMMON BEING DIARRHEA, RASH, NAUSEA, FATIGUE, HEADACHE, ANOREXIA, VOMITING, CONSIPATION AND TASTE CHANGE. FORTUNATELY MOST OF THESE WERE MILD GRADE ONE OR TWO. SO NOW I'LL TALK ABOUT THE PHASE THREE RANDOMIZED DOUBLE BLIND PLACEBO CONTROL TRIAL. ALSO KNOWN AS THE ZETA TRIAL. FIRST PATIENT WAS ENROLL INDEED DECEMBER 2006 AND THE LAST PATIENT WAS RAPPED ORDER OF MICRONSIZE INDEED NOVEMBER 2007. THE DATA CUT OFF WAS JULY OF 2009. THE MEDIAN DURATION OF FOLLOW UP WAS 24 MONTHS. THERE WERE 331 PATIENTS RAPPED ORDER OF MICRONSIZED. --RANDOMIZED. IT WAS A TWO TO ONE RANDOMIZED TRIAL--231 GETTING RANDOMIZED TRIAL DETAILS NIB AND OTHERS GETTING PLACEBO THAT. I WERE FOLLOWED FOR PROGRESSION, THEY DISCONTINUED THE BLINDED TREATMENT AND PATIENT HIS THE OPTION OF CROSSING OVER TO VAN DETAILS NIB IF AT A WERE IN THE PLACEBO ARM OR CONTINUING THE VAN DETAILS NIB IF THEY WERE IN THE TREATMENT ARM, IF THE INVESTIGATOR FELT THEY WERE STILL ACHIEVING CLINICAL BENEFIT. AND THEN THEY WERE FOLLOWED FOR SURVIVAL. THE PRIMARY END POINT OF THIS STUDY WAS PROGRESSION FREE SURVIVAL BASED ON RESIST ASSESSMENTS. THE SECONDARY ASSESS WANTS INCLUDED OBJECTIVE RESPONSE RATES, DISEASE CONTROL RATE AT 24 WEEKS, BIOCHEMICAL RESPONSE OVERALL SURVIVAL, TIME TO WORSENING PAIN AND SAFETY AND TOLERABILITY. HERE ARE THE PATIENT DEMOGRAPHICS IN BASELINE CHARACTERISTICS. THEY'RE WELL MATCHED AS YOU CAN SEE. MOST OF THE PATIENTS HAD SPORADIC DISEASE. MOST, CLOSE TO ALL OF THEM HAD METASTATIC DISEASE, BUT UNFORTUNATELY IN STATUS OF THE RETINAL LOCATION MUTATION WASN'T KNOWN IN 40% IN BOTH ARMS. SO AGAIN, DIFFICULT TO DETERMINE WHETHER OR NOT RESPONSE CORRELATED TO TUMOR GENOTYPE. AND HERE'S THE SUMMARY OF THE PROGRESSION FREE ANALYSIS. IN THE VAN DETAILS NIB ARM THERE WERE 73 EVENTS IN THE PLACEBO ARM, 51 EVENTS WITH THE HAZARD RATIO OF 0.46. AND THIS IS HIGHLY STATISTICALLY SIGNIFICANT. THEY LOOKED AT OTHER PREDEFINED SECONDARY SENSITIVITY ANALYSIS WHICH EXCLUDED THE OPEN LABEL PHASE AND IF THEY JUST LOOKED AT THE INVESTIGATOR ASSESSMENTS AND THE HAZARD RATIOS WERE STILL SIGNIFICANTLY BETTER FOR VAN DETAILS NIB VERSES PLACEBO. AND HERE'S THE CAP LANMEYER CURVE SHOWING THE DIFFERENCE IN PROGRESSION FREE SURVIVAL FOR VANDETNIB AND PLACENTA SIB O. THE MEDIAN PROGRESSION FREE SURVIVAL IN THE PATIENTS WAS NOT REACH INDEED THE TIME OF DATA CUT OFF AND IN PLACENTA SUBIN O IT WAS--PLACEBOA IT WAS 19 MONTHS. HERE ARE THE OBJECTIVE TREATMENTS, 45% OF PATIENTS IN THE VANDETNIB ARM HAD AN OBJECTIVE PARTIAL RESPONSE. AND 13% OF PATIENTS IN THE PLACEBO ARM HAD AN OBJECTIVE PARTIAL RESPONSE OF NOTE, 12 OF 13 OF THOSE RESPONSES IN THE PLACEBO ARM OCCURRED WHILED PATIENTS WERE RECEIVING VANDETNIB IN THE OPEN LABEL PHASE THE OBJECTIVE RESPONSES WERE DURABLE BUT THE MEDIAN RESPONSE NOT REACHED AT 24 MONTHS OF FOLLOW UP. CALCTONEIN AND CEA LEVELS WERE ALSO LOOKED AT IN THIS STUDY AND AS YOU CAN SEE, 69% OF PATIENTS AND 52% OF PATIENTS IN THE VAN DETAILS NIB ARM HAD A DECREASE OF CALCTONEIN BY AT LEAST 50%. COMPARED TO PLACEBO WHICH WAS STATIST LIKELY SIGNIFICANT: THE MEDIAN DURATION OF TREATMENT IN THE RANDOMIZED PHASE WAS 90 WEEKS FOR VAN DETAILS NIB AND 40 WEEKS FOR PLACEBO, THE MOST COMMON ADVERSE EVENTS OF ANY GRADE THAT WERE MORE FREQUENT IN THE VAN DETAILS NIB ARM WERE DIARRHEA, RASH, NAUSEA AND HYPERTENSION. MORE PATIENTS REQUIRE DOSE REDUCTIONS OF VAN DET NIB COMPARED TO PLACEBO, 35% ACTUALLY. AND THERE WERE 28 PATIENTS IN THE VAN DETAILS NIB ARM AND THREE IN THE PLACEBO ARM WHO DISCONTINUED RANDOMIZED TRIAL AUTOMATICKIZED TREATMENT DO YOU TO AN ADVERSE EVENT. HERE ARE THE MOST COMMON GRADE THREE ADVERSE EVENTS THAT OCCURRED IN AT LEAST TWO% OF PATIENTS IN EITHER ARM DIARIA, HYPERTENSION, PROLONGED QTC, FATIGUE, DECREASED APPETITE, THE MOST COMMON. THE QTC PROM OLOGIATION HAS BECOME AN ISSUE WITH THE FDA AND AS FAR AS FDA APPROVAL IS CONCERNED, THIS DRUG DID GO ON TO GET ARUED BY THE FDA FOR THE TREATMENT OF ADVANCED MADULARY THYROID CANCER, BUT IT'S PRESCRIBED7<-7 UNDER A R. E. M. S. PROGRAM WHICH REQUIRES TRAINING OF THE PRACTITIONER PRIOR TO PRESCRIBING IT IN ORDER TO MAKE SURE THEY REALIZE THE RISK OF Q. T. C. AND AFT RASWRENNICCA IS DOING A STUDY TO LOOK AT THE PROLONGED RISK OF Q. T. C. PROLONGATION WITH THE LOWER DOSE TREATMENT. SO IN CONCLUSION AND THIS PHASE THREE TRIAL, THE VAN DETAILS NIB DEMONSTRATED THE ADVANTAGE OF PROGRESSION PREE SURVIVAL VERSES PLACEBO. THERE WERE OTHER ADVANTAGES FOR VAN DETAILS NIB INCLUDING OBJECTIVE RESPONSE RATES, DISEASE CONTROL RATE, BIOCHEMICAL RESPONSE, TIME TO WORSENING OF PAIN, ADVERSE EVENTS WERE GENERALLY MANAGEABLE, FOR TREATMENT FOR VAN DETNIB FOR PROLONGED PERIODS OF TIME AND THIS LED TO THE FDA APPROVAL OF VAN DETNIB FOR TREATMENT OF SYMPTOMATIC OR MADULARY THYROID CANCER AND LOCALLY ADVANCED OR METASTATIC DISEASE. THE SUCCESS WITH VAN DETNIB IN ADULTS HAS BEEN LED TO ITS USE IN MEDIATE RICK PATIENTS. AS DR. WELLS MENTIONED, YOU CAN CURE THESE CHILDREN IF DO YOU A PROPHYLACTIC THYROIDECTOMY BUT UNFORTUNATELY THERE IS NOT ALWAYS THE CASE SO THERE ARE PATIENTS OUT THERE WITH THIS DISEASE WHO NEED TO BE TREATED. SO THE OBJECTIVE OF THE PEDIATRIC STUDY WHICH IS CURRENTLY BEING CONDUCTED HERE BY BRIG EDUCATIONALLA WEEDER MAN AND WAS INITIALLY STARTED BY FRANK BAYLESS AND INLIZ BETH FOX PRIOR TO--ELIZABETH FOX PRIOR TO THEIR DEPART SURTO ASSESS THE MARKERS TO DETERMINE THE MAXIMUM DOSE, SAFETY, AND TOLERABILITY AND TO LOOK AT THE PLASMA PHARMA CO INETTICS AND DYNAMICS. THE SECONDARY OBJECTIVES ARE PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL AND TISSUE STUDIES. THE PATIENTS ELIGIBLE FOR THIS ARE CHILDREN IN'D LES ENS WITH UNRESECTABLE MADULARY THYROID CANCER WITH MEASURABLE DISEASE. THERE WAS A PHASE ONE COMPONENT TO DETERMINE THE DOSE, THE SAFE DOSE LEVEL AS WELL AS A SINGLE STAGE PHASE TWO TO LOOK AT THE RESPONSE RATES. 16 PATIENTS WERE ENROLLED WITH THE MEDIAN AGE OF 15 [CHECK] THEY HAD--THEY HAD VARIOUS METASTATIC SITES AND 15 OF THOSE PATIENTS HAD THE M-918 T MUTATION ASSOCIATE WIDE M. E. N. TWO B WITH ONE PATIENT WITH A POLYMORPHISM. THE MEDIAN RANGE OR THE MEDIAN NUMBER OF CYCLE SYSTEM 24, WITH A RANGE OF TWO TO 48. WHAT THEY FOUND WAS THAT THE PATIENTS TOLERATED THE VANDETAILS NIB WELL WITH NO TOXICITY AND THIS SHOWS THERE WERE RESPONSES SIMILAR TO THOSE SCENE IN ADULTS. >> JUST TO POINT OUT THESE PATIENTS THAT DR. WELLS DESCRIBED HAVE M. E. N. TWO B. THEY HAVE THOSE ACTIVATED MUTATIONS IN THE RET PROTOONK - GENE THAT CAUSED THE SYNDROME OF MATULARY CANCER, CORS NOMAS AND SKELETAL ABNORMALITIES. AND HERE'S THE WATER FALL FLOTFOR THE PEDIATRIC STUDY. THESE ARE ALL RESPONDERS, AND THE REST OF THE PATIENTS DID APPEAR TO HAVE SOME DEGREE OF TUMOR RESPONSE WITH ONLY ONE HAVING PROGRESSIONIVE DISEASE AS BEST RESPONSE. >> SO FINALLY I'M JUST GOING TO MENTION THE CLINICAL TRIALS THAT WE HAVE ONGOING HERE IN THE MEDICAL ONCOLOGY BRANCH FOR THYROID CANCER. THE FIRST TRIAL IS TARGETED PHASE ONE-TWO TRIAL LOOKING AT VANDETAILS NIB PLUS THE PROTEOSOME INHIBITOR AND THE SOLID TUMORS AND THEN THE FOCUS IS ON HEREDITARY SPORADIC LOCALLY ADVANCED METASTATIC MADULARY THYROID CANCER. THIS IS BASED ON PRECLINICAL EVIDENCE THAT THE ADDITION OF MORTOC NIB ENHANCES ACTIVITY AND MADULARY THYROID CANCER CELL LINES. WE INCLUDED PATIENTS WITH ADVANCED SOLID TUMORS GOOD PERFORMANCE STATUS AND ADEQUATE ORGAN FUNCTION AND THERE WAS A DOSE ESCALATION SCHEMA OF THE COMBINATION OF VAN DETAILS NIB AND BORTUZMIB. THE PHASE ONE ENROLLED FROM MARCH OF 09 TO NOVEMBER 2010 AND THE PHASE ONE PORTION IS COMPLETE AND THE DATA THAT I MENTIONED HERE AS OF MAY OF 2011. THIS SHOWS THE DOSE ESKACCT CLAIGZ SCHEMA OF THE VETMIB DOSE AND MORTAZAMIB DOSE, THREE PATES WERE ENROLLED AT LEVEL ONE, WITH DOSE AT LEVEL, TWO, THREE, FOUR, AND THIS SHOWS THAT 23 PATIENTS TOTAL--I'M SORRY THAT DOESN'T MAKE SINCE. THIS SHOWS THAT 13 OF THE PATIENTS GOT TO DOSE LEVEL THREE AND 10 OF THE PATIENTS GOT TO DOSE LEVEL FOUR BECAUSE THERE WAS INTRANSLATIONAL RESEARCH PATIENT DOSE ESCALATION DONE THERE WERE 21 PATIENTS, MOST OF THOSE, 17 HAD MADULARY THYROID CANCER WITH TWO CARTICLE CARC NOME AS, ONE FOLLICULAR THYROID CANCER AND ONE ENDOCRINE TUMOR. N. O. S. PATIENT RECEIVED FOUR CYCLES OF COMBINATION VANDETNIB AND MORTEZAMIB, AND THE RANGE WAS BETWEEN ONE AND 10 CYCLES OF OF A COMBINATION AND THERE WAS AN OPTIONAL CONTINUATION OF VANDETNIB ALONE AFTER SIX CYCLES OF COMBINATION AND UNACCEPTABLE COXISITY THAT WAS THOUGHT TO BE BE RELATED TO THE MORTEZAMIB. HERE ARE THE GRADE 34 ADVERSE EVENTS IN MORE THAN FIVE% OF PATIENTS REGUARDLESS OF CAUSALITY. LIM FOE PENIA, HYPERTENSION, FATIGUE, DISCIPLINARY RARA AND HYPER K-LEAMIA WERE MOST COMMON. AND I DON'T KNOW IF YOU REMEMBER THE PRIOR TOXICITIES I SHOWED YOU BUT THE ADDITIONAL ONES THAT WE SEE HERE ARE LIMP FOE PENIA, THOM BOW CYTOPENIA IS HYPER K-LEAMIA ALTHOUGH THESE NUMBERS ARE SMALL, OUR ONE DOSE LIMITING TOX ISOTOPEIT WAS THROMBOW CYTOPENIA AND PATIENT AT DOSE LEVEL THREE. SO, WE DETERMINED THE MTD OF COMBINATION THERAPY IS VAN DETAILS NIB 300-MILLIGRAMS DAILY, ORALLY AND ONE OPINION 3-MILLIGRAMS, IV DAYS ONE, FOUR, EIGHT AND 11 AND CURRENTLY WE HAVE ANON GOING PHASE TWO TRIAL TO DEEMERGING IT THE COMBINATION OF VORTEES NIB IS SUPERIOR TO VANDETAILS NIB, LONE AND FINALLY WE HAVE A TRIAL IN ANAPLASTIC THYROID CANCER IT'S A PHASE ONE, TWO TRIAL IN ADULTS WITH SOLID TUMORS WITH A FOCUS ON ANAPLASTIC THYROID CANCER. CO OBULINSA TUBEULAR INHIBITOR THAT HAS ANTITUMOR INFECTS IN VIVO AND INVITRO. AND IT'S FLOOD FLOW TO THE TUMOR. THE PHASE ONE STUDY DESIGN IS DOSE ESCALATION OF SIS PLATIN DAY ONE AND CRIBUE LYNN DAY TWO AND THREE EVERY 21 DAYS. THE STUDY OPENED JANUARY 2011 AND TO THIS POINT HAS ENROLLED 10 PATIENTS NINE OF WHOM HAVE AN PLASTIC THYROID CANCER AND WE'RE ENROLLING AT THE FINAL DOSE LEVEL. SO ONCE THE MTD IS REACHED,AISE PHASE TWO TRIAL WILL COMMENCE RANDOMIZING PATIENTS TO SIS PLATIN, VERSES SIS PLATEPIGENETIC ALONE TO DETERMINE IF THERE IS A PEN FIT--BENEFIT. THAT'S IT. I DON'T KNOW HOW TO GET RID OF THIS. [ APPLAUSE ] >> YOU MENTIONED THE DIAGNOSIS, ARE YOU USING NICLEAR SCAN WITH THE ONE, TWORKS THREE OR ULTRASOUND FOLLOWED WITH A NEEDLE ASPIRATION BIOPSY? >> ARE YOU TALKING ABOUT FOR THE DIAGNOSIS OF DIFFERENTIATED THYROID CANCER? >> YES. >> THE TYPICALLY THE DIAGNOSIS IS DONE BY ULTRASOUND AND FINE NEEDLE ASPIRATION AND YOU KNOW YOU DON'T NEED TO DO AN ULTRASOUND ON EVERY THYROID NODULE, JUST THE ONES THAT ARE THERE FOR A PROLONGED PERIOD OF TIME OR APPEAR TO BE GROWING OR THAT ARE CLEARLY OVERA CENTIMETER AND NOT THOUGHT TO BE GOITER. >> AND YOU MENTIONED YOU ARE USING CT TO FOLLOW UP THE SHRINKAGE OF THE TUMOR. >> YES. >> IS THE SHRINKAGE SIMILAR FOR THE PRIMARY TUMOR AS WELL AS METASTATIC SITES? >> WELL, TYPICALLY IN PATIENTS WITH ADVANCED DISEASE, THEY'VE HAD THE PRIMARY TUMOR RESECTED AND THEY'VE REOCCURRED. SO WE DON'T HAVE MANY PATIENTS THAT HAVE A PRIMARY TUMOR PRESENT. I CAN SAY THAT IN THE--I THINK I HAD ONE PATIENT WHO HAD A PRIMARY TUMOR, AS PRES SPENT HE HAD THE SAME RESPONSE IN THE PRIMARY AS WELL AS THE METASTATIC SITES. >> EXCELLENT STUDY, THANK YOU. >> GIVEN THE RECENT DATA WITH THE SIS PLATIN AND RADIATION, HAS THERE BEEN ANY THOUGHT TO COMBINING DRUGS LIKE VANDETAILS NIB WITH SIS PLATIN OR RADIATION EARLIER ON IN TREATMENT? >> FOR ANAPLASTIC OR FOR MADULARY? SO I THINK THE--THE RADIATION DATA THAT DR. WELLS SHOWED US FOR ANNA PLASTIC THYROID CANCER AND THE VAN DETAILS NIB IS OHM USE INDEED MADULARY THYROID-- >> NO, NO, IT HASN'T. NOT THAT I KNOW OF AT LEAST. >> ANY HAVE ANY QUESTIONS FOR DR. WELLS? >> I HAVE A FEW QUESTIONS, I KNOW THE PATIENTS DON'T RESPOND FOREVER, SO WHAT IS THE EXPECTATION WHEN THEY PROGRESS ON VAN DETAILS NIB AND DO WE KNOW WHAT THE MECHANISMS OF RESISTANCE ARE AND WHAT THE NEXT TREATMENT OPTIONS WOULD BE FOR PATIENTS. >> NO, WE UNFORTUNATELY DON'T KNOW WHAT THE MECHANISMS OF RESPONSE OR RESISTANCE ARE. UNFORTUNATELY, TISSUE STUDIES HAVEN'T BEEN DONE THAT HAVE GIVEN US THAT INFORMATION. TYPICALLY IF THE PATIENT PROGRESSES, ONCE THEY PROGRESS, YOU KNOW WE TRY TO DO DIRECTIVE LOCAL THERAPY AND ACTIVITIES AND PROJECTS FETAL COMPARTMENT THAT'S POSSIBLE, OR THEY GO ON TO THE NEXT CLINICAL TRIAL. >> THERE'S BEEN A REAL PROBLEM, I THINK IN A LOLL LOT OF SOLID TUMORS AND THIS, THAT'S UNFORTUNATELY BECAUSE OF THE MUTATIONS THAT CAUSE THESE TUMORS, HAVE YOU SOMETHING TO START WITH. I THINK WHAT'S GOING TO HAVE TO BE DONE IS TO BIOPSY THESE PATIENTS BEFORE THEY GO ON A STUDY AND CERTAINLY AT THE TIME, IF THEY PROGRESS, NOT GOING TO ARGUE THEY SHOULD BE BIOPSY WHEN THEY REACH THE MAXIMUM LEVEL OF THE DRUG BUT WE DON'T KNOW ANYTHING. THERE'S NOT A SINGLE CLINICAL TRIAL WHERE IT WAS DATA FROM TUMOR TO INDICATE WHO WOULD LIKELY RESPOND AND ESPECIALLY WHAT THERAPY OUGHT TO BE USED. THERE'S BEEN ONE COMPLETE RESPONSE OF ALL THESE DRUGS, USED TO TREAT THESE PATIENTS AND ONE CLINICAL TRIAL. MOST PARTIAL RESPONSES, MOST PEOPLE BREAK THROUGH THE THERAPY, SO WE'RE KIND OF IN A PERIOD WHERE THE NEXT STEP IS REALLY GOING TO BE GETTING THE MOLECULAR DATA, THE NCI CLINAL CENTER IS PROBABLY THE ONLY PLACE THAT COULD DO THIS. CT LIVER BIOPSY ON THE OUTSIDE, IT'S FOUR OR $5000 A CRACK. YOU DO IT THREE TIMES IT'S VERY EXPENSIVE TO DO IT. I THINK IT WILL BE UNETHICAL NOT TO GET THESE DATA ON PATIENTS. IT IS A CRITICAL PART OF THE TRIAL. IT'S JUST NOT DONE. >> GOING BACK TO COMMENTS REGUARDING INCREASING INCIDENCE OF THYROID CANCERS OVER THE PAST SEVERAL YEARS, AND YOUR REFERENCE TO THE EFFECTS OF RADIATION, COULD YOU COMMENT ON ANY DATA THAT RELATES TO THYROID CANCER WITH REGUARD TO DIAGNOSISTIC USE OF RADIATION, THERE'S BEEN SOME CONCERN IN TERMS OF RADIATION EXPOSURE WITH CT SCANNING DIAGNOSTIC PROCEDURES AND OTHER TYPES OF RADIATION EXPOSURE IN THE CONTEXT OF DIAGNOSIST PROCEDURES, COULD YOU PLEASE COMMENT ON THAT. >> I THINK CURRENTLY IT'S REALLY NOT KNOWN WHETHER VERY LOW DOSES OF RADIATION USED IN DIAGNOTTIC PROCEDURES. ARE IMPORTANT IN CAUSING INCREASE IN THIS CANCER OR NOT. THIS HAS BEEN A CONCERN ON SEVERAL PEOPLE. IT WAS ESPECIALLY BROUGHT INTO LIGHT WITH THE CHERNOBYL ACCIDENT. THIS IS A HIGHER RADIATION ACCIDENT, AND ALSO YOUNG CHILDREN WHO ARE RADIATED FOR CROUP YEARS AGO WITH LOW DOSE RADIATION WHEN THEY BECAME ADULTS BECAUSE SOME DEVELOP THYROID CARC THOMEA BUT AT PRESENT IT'S COMPLETELY UNKNOWN, AND THE RADIATION EXPOSURE PLAYS IN THIS, IT WAS A STUDY THAT ACTUALLY ELAINE RON MENTIONED STARTED, WITH YOUR A COLLEAGUE AT THE UNIVERSITY OF PITTSBURGH TO GO BACK OVER TIME AND LOOK AT THE INCIDENCE OF PTC TRANSLOCATIONS IN TUMORS 50 YEARS AGO, COMPARED TO 25 YEARS AGO, TO GET AN IDEA IF THERE'S AN INCREASING INCIDENCE OF THAT BIOLOGIC MARKER WHICH MIGHT GIVE SOME INDEX OR INDICATION THAT THIS IS CAUSED, IF THIS IS INCREASED RADIATION EXPOSURE BUT IT NOW IS JUST AN OPEN QUESTION. >> I THINK IN ADDITION TO THAT, THERE HAVE BEEN MULTIPLE STUDIES THAT HAVE SHOWN HAT RISK IS HIGHER BEFORE THE AGE OF 14 OR 15 YEARS OLD. SO, AND I KNOW THAT THERE HAVE BEEN MULTIPLE META-ANALYSIS LOOKING AT THIS ISSUE AND THEY'VE VARIED IN THEIR CONCLUSIONS, SO I THINK IT'S STILL UNCLEAR. >> THANK YOU. >> I JUST WANT TO ASK A QUICK QUESTION ABOUT VANDETNIB AND YOUR EXPERIENCE WITH PATIENTS ON THE TRIAL. AT LEAST FOR THE PHASE THREE, WHERE YOU SAID THAT PATIENTS THAT PROGRESSION COULD STAY ON DRUGS IF THEY WERE SER CEIVED TO HAVE CLEANICAL BENEFIT, DO YOU KNOW HOW MANY PATIENTS STAYED ON DRUG AND THEN SECOND QUESTION IS, HAVE YOU SEEN A LOT OF THE EXPLOSIVE GROWTH WHEN YOU COME OFF DRUG BECAUSE OF ALL THE TO ROSINEI KINASE UPREGULATED WITH SUNET NIB AND OTHER TYROSEEN KINASE INHIBITORS? >> I CAPTAIN RECALL, IT WOULD BE ANECDOTAL OF THE NUMBER OF PATIENTS WHO GET THE GROWTH WHEN THEY COME OFF THE DRUG. I CAN IMAGINE IT WOULD HAPPEN. IT HASN'T BEEN MY PERSONAL EXPERIENCE THAT IT OCCURS. THE FIRST PART OF YOUR QUESTION ADDRESSED THE DECISION TO KEEP THE PATIENTS ON THE DRUG ONCE THEY PROGRESSED. THIS IS LEFT UP TO THE DOCTOR TREATING THE PATIENT WHETHER HE THOUGHT IT WAS USEFUL OR NOT. I USED TO FEEL THAT THIS WAS PROBABLILY NOT AN IMPORTANT THING TO DID, BUT DATA WHICH THE DOCTOR GENERATED ABOUT RATE OF GROWTH OF THESE TUMORS AND WHETHER OR NOT THEY'RE REALLY TWO THINGS GOING ON AS FAR AS NUMBER OF TUMOR CELLS JUST REALLY HOLDING DOWN WITH TREATMENT, MAYBE ON A PERMANENT BASIS AND THOSE THAT BREAK THROUGH THE THERAPY WHETHER IT'S JUSTIFIABLE TO KEEP TREATING THESE PATIENTS HAS SOME SUBSTANTIAL DATA THAT YOU COULD HOW TO CHOOSE THOSE AND PICK THEM OUT IS NOT KNOWN. IT WAS JUST LEFT UP AS AN INDIVIDUAL PERSONAL DECISION WITH NO REAL CONCRETE MOLECULAR CLINICAL DATA. >> IT'S INTERESTING THAT YOU KNOW IN SEVERAL PATIENTS WHAT YOU SEE IS NOT AN EXPLOWS OF DISEASE WHEN THEY PROGRESSION MEANING THAT ALL OF THE TARGET LESIONS DON'T START INCREASING. THEY DON'T NECESSARILY DEVELOP NEW LESIONS BUT ONE OF THE LESIONS WILL START GROWING AND THE REST OF THEM REMAIN STABLE AND YOU KNOW WHEN THERE'S NO OTHER THERAPEUTIC OPTION FOR THE PATIENT AND THEY HAVE ONE SMALL LESION THAT'S GROWING WHILE THE REMAINDER OF THEIR DISEASE IS STAYING STABLE, IT'S REALLY HARD TO JUSTIFY TAKING THEM OFF OF IT. SO, I ATTENDED TO KEEP PEOPLE ON IF IT'S JUST A MINIMAL AMOUNT OF PROGRESSION IN ONE AREA; THANK YOU. >> THANK YOU ALL. >> [ APPLAUSE ]