1 00:00:05,280 --> 00:00:10,560 >> WELCOME TO THE NEXT TO THE 2 00:00:10,560 --> 00:00:13,920 LAST SESSION OF THE 21st YEAR OF 3 00:00:13,920 --> 00:00:15,240 THE DEMYSTIFYING MEDICINE COURSE 4 00:00:15,240 --> 00:00:22,360 AT THE NATIONAL INSTITUTES OF 5 00:00:22,360 --> 00:00:22,600 HEALTH. 6 00:00:22,600 --> 00:00:27,800 WE HAVE ORGANIZED THIS PROGRAM 7 00:00:27,800 --> 00:00:28,200 FOR YOU. 8 00:00:28,200 --> 00:00:30,400 IT HAS THE GOAL OF BRIDGING 9 00:00:30,400 --> 00:00:35,120 EXCITING DEVELOPMENTS IN BIOLOGY 10 00:00:35,120 --> 00:00:36,640 AND ENGINEERING WITH MEDICINE, 11 00:00:36,640 --> 00:00:41,760 BRIDGING THE GAP. 12 00:00:41,760 --> 00:00:43,920 NOW, THIS IS A COURSE IN BRIDGE 13 00:00:43,920 --> 00:00:44,160 BUILDING. 14 00:00:44,160 --> 00:00:50,560 DURING THE YEAR WE HAVE BRIDGED 15 00:00:50,560 --> 00:00:53,760 EXTRAORDINARY GAPS TO SPACE, TO 16 00:00:53,760 --> 00:00:57,520 BIO TECHNOLOGY, TO A GREAT 17 00:00:57,520 --> 00:00:59,320 VARIETY OF AREAS INCLUDING 18 00:00:59,320 --> 00:01:01,160 LANGUAGE BUT THE PRINCIPLE OF 19 00:01:01,160 --> 00:01:04,000 THE MAIN ACTIVITY IN 20 00:01:04,000 --> 00:01:10,320 DEMYSTIFYING MEDICINE BASICALLY 21 00:01:10,320 --> 00:01:12,200 REPLICATED TO WHAT WE REFER TO 22 00:01:12,200 --> 00:01:17,440 AS OLD FASHIONED GRAND MEDICAL 23 00:01:17,440 --> 00:01:18,080 GROUNDS. 24 00:01:18,080 --> 00:01:19,720 A PATIENT WITH THEIR DISEASE AND 25 00:01:19,720 --> 00:01:23,200 SOMEONE PUTS A HUMAN FACE ON THE 26 00:01:23,200 --> 00:01:23,760 DISEASE. 27 00:01:23,760 --> 00:01:24,960 THEN A PHYSICIAN SCIENTIST 28 00:01:24,960 --> 00:01:26,760 DESCRIBES WHAT THE DISEASE IS 29 00:01:26,760 --> 00:01:29,160 AND WHAT THEY'RE DOING ABOUT IT 30 00:01:29,160 --> 00:01:31,960 AND THEN A BASIC SCIENTIST TELLS 31 00:01:31,960 --> 00:01:33,240 US MORE OR LESS WHAT WE KNOW, 32 00:01:33,240 --> 00:01:35,840 WHAT WE NEED TO KNOW AND THAT'S 33 00:01:35,840 --> 00:01:40,000 FOLLOWED BY A ROBUST QUESTION 34 00:01:40,000 --> 00:01:42,160 AND ANSWER AND DISCUSSION. 35 00:01:42,160 --> 00:01:46,440 SO THESE TWO GENTLEMEN ON THE 36 00:01:46,440 --> 00:01:50,560 BRIDGE ARE DISCUSSING WHAT IS IT 37 00:01:50,560 --> 00:01:51,960 ABOUT THE BENIGN TUMORS OF 38 00:01:51,960 --> 00:01:54,160 CHILDREN, SOME OF THEM. 39 00:01:54,160 --> 00:01:58,760 SOME OF THEM TURN MALIGNANT, 40 00:01:58,760 --> 00:02:00,160 SOME ARE INHERITED. 41 00:02:00,160 --> 00:02:07,000 SOME PRODUCE LOCAL AFFECT THAT 42 00:02:07,000 --> 00:02:08,480 REQUIRE TREATMENT, MORE OFTEN 43 00:02:08,480 --> 00:02:10,160 THAN NOT SURGERY AND SOME 44 00:02:10,160 --> 00:02:13,720 PRESENT PROBLEMS THAT CANNOT BE 45 00:02:13,720 --> 00:02:15,120 ADDRESSED BY SURGERY AND WHAT IF 46 00:02:15,120 --> 00:02:17,760 ANYTHING CAN WE DO ABOUT THEM 47 00:02:17,760 --> 00:02:23,400 AND ARE THEY PRECURSERS OF 48 00:02:23,400 --> 00:02:23,800 MALIGNANT DISEASE. 49 00:02:23,800 --> 00:02:28,760 THE WORD FOR TUMOR IS OMA. 50 00:02:28,760 --> 00:02:36,000 WE HAVE FIBROMAS AND TODAY WE'RE 51 00:02:36,000 --> 00:02:46,520 DISCUSSING FIBROMATOSIS AND SOME 52 00:02:46,520 --> 00:02:49,880 ARE INHERITED AND SOME ARE MAN 53 00:02:49,880 --> 00:02:53,560 MANIFESTED IN CHILDREN AND YOUNG 54 00:02:53,560 --> 00:02:53,840 ADULTS. 55 00:02:53,840 --> 00:02:55,560 THEY'VE BEEN DESCRIBED 56 00:02:55,560 --> 00:02:56,560 CLINICALLY AND PATH OWE 57 00:02:56,560 --> 00:02:59,800 LOGICALLY AND ASIDE FROM 58 00:02:59,800 --> 00:03:02,120 SURGERY, VERY LITTLE HAS BEEN 59 00:03:02,120 --> 00:03:04,000 POSSIBLE IN THE WAY OF EFFECTIVE 60 00:03:04,000 --> 00:03:09,120 THERAPY UNTIL TODAY. 61 00:03:09,120 --> 00:03:15,480 AND SO TODAY'S SPEAKERS ARE 62 00:03:15,480 --> 00:03:16,440 RESPONSIBLE FOR TREMENDOUS 63 00:03:16,440 --> 00:03:22,680 ADVANCES IN UNDERSTANDING THE 64 00:03:22,680 --> 00:03:24,160 MOLECULAR BASIS OF 65 00:03:24,160 --> 00:03:24,800 NEUROFIBROMATOSIS TYPE-1 AND 66 00:03:24,800 --> 00:03:27,600 OTHER SUCH TUMORS IN CHILDREN. 67 00:03:27,600 --> 00:03:29,000 SOME CHARACTERISTICS ON THIS 68 00:03:29,000 --> 00:03:30,160 SLIDE WILL BE DISCUSSED IN MUCH 69 00:03:30,160 --> 00:03:42,280 GREATER DETAIL SO I'M GOING TO 70 00:03:42,280 --> 00:03:46,320 SKIP OVER IT THE FIRST IS 71 00:03:46,320 --> 00:03:49,160 BRIGITTE WIDEMAN WHERE SHE 72 00:03:49,160 --> 00:03:51,240 GRADUATED IN GERMANY AND CAME TO 73 00:03:51,240 --> 00:03:53,640 THE NIH AS A FELLOW IN 74 00:03:53,640 --> 00:03:56,160 HEMATOLOGY AND ONCOLOGY. 75 00:03:56,160 --> 00:03:57,840 WE'RE ALL DELIGHTED THE STAYED 76 00:03:57,840 --> 00:03:59,960 HERE EVER SINCE. 77 00:03:59,960 --> 00:04:02,320 SHE ACHIEVED TENURE IN 2009 AND 78 00:04:02,320 --> 00:04:07,200 CURRENTLY IS THE NCI HEAD OF 79 00:04:07,200 --> 00:04:08,040 PHARMACOLOGY AND EXPERIMENTAL 80 00:04:08,040 --> 00:04:09,080 THERAPEUTIC SECTION. 81 00:04:09,080 --> 00:04:12,800 SHE'S THE CHIEF OF PEDIATRIC 82 00:04:12,800 --> 00:04:26,120 ONCOLOGY BRANCH AND A CLINICAL 83 00:04:26,120 --> 00:04:28,000 DEPUTY DIRECTOR. 84 00:04:28,000 --> 00:04:30,160 SHE WAS INVOLVED IN EARLY TRIALS 85 00:04:30,160 --> 00:04:35,360 IN CHILDREN WITH ADULTS WITH 86 00:04:35,360 --> 00:04:39,960 REFACTORY CANCERS AND TUMOR 87 00:04:39,960 --> 00:04:41,160 PREDISPOSITION SYNDROME SUCH AS 88 00:04:41,160 --> 00:04:44,920 THE ONE TO BE DISCUSSED TODAY, 89 00:04:44,920 --> 00:04:45,560 NEUROFIBROMATOSIS TYPE-1. 90 00:04:45,560 --> 00:04:49,040 WITHIN THE PAST YEAR OR TWO HER 91 00:04:49,040 --> 00:04:55,880 WORK AND WITH HER COLLEAGUES HAS 92 00:04:55,880 --> 00:04:57,080 ATTRACTED ENORMOUS AND 93 00:04:57,080 --> 00:04:58,160 APPRECIATION. 94 00:04:58,160 --> 00:04:59,680 THEY'RE RESPONSIBLE FOR THE 95 00:04:59,680 --> 00:05:04,040 FIRST FDA APPROVED TREATMENT FOR 96 00:05:04,040 --> 00:05:11,280 NEUROFIBROMATOSIS TYPE-1. 97 00:05:11,280 --> 00:05:14,480 AND RECEIVED AN AWARD WITHIN THE 98 00:05:14,480 --> 00:05:17,480 TOP 10 CLINICAL RESEARCH AWARDS 99 00:05:17,480 --> 00:05:19,040 FROM THE CLINICAL RESEARCH 100 00:05:19,040 --> 00:05:19,240 FORUM. 101 00:05:19,240 --> 00:05:21,280 THIS IS A BIG DEAL. 102 00:05:21,280 --> 00:05:22,960 SHE WAS ELECTED TO THE 103 00:05:22,960 --> 00:05:23,640 ASSOCIATION OF AMERICAN 104 00:05:23,640 --> 00:05:27,960 PHYSICIANS AND GAVE AN 105 00:05:27,960 --> 00:05:33,760 OUTSTANDING LECTURE AT THE NIH. 106 00:05:33,760 --> 00:05:36,040 SHE HAS PLAYED A PART IN 107 00:05:36,040 --> 00:05:36,800 DEVELOPING MULTIPLE CLINICAL 108 00:05:36,800 --> 00:05:41,320 TRIALS OF NEW INVESTIGATIONAL 109 00:05:41,320 --> 00:05:42,120 AGENTS. 110 00:05:42,120 --> 00:05:48,000 IN PEDIATRIC REFRACTORY CANCERS 111 00:05:48,000 --> 00:05:48,600 AS WELL AS NEUROFIBROMATOSIS 112 00:05:48,600 --> 00:05:51,960 TYPE-1. 113 00:05:51,960 --> 00:05:56,800 THE SECOND SPEAKER IS JACK SHERN 114 00:05:56,800 --> 00:05:58,560 WHO GRADUATE FROM THE MEDICAL 115 00:05:58,560 --> 00:06:00,640 COLLEGE OF GEORGIA. 116 00:06:00,640 --> 00:06:03,560 TOOK HIS PEDIATRIC RESIDENCY AT 117 00:06:03,560 --> 00:06:06,200 THE UNIVERSITY OF CHICAGO, 118 00:06:06,200 --> 00:06:08,360 CHILDREN'S HOSPITAL AND THEN 119 00:06:08,360 --> 00:06:11,200 TRAINED IN PEDIATRIC HEMATOLOGY 120 00:06:11,200 --> 00:06:14,920 AND ONCOLOGY AT NIH AT THE NCI. 121 00:06:14,920 --> 00:06:16,840 HE'S IN THE CANCER RESEARCH 122 00:06:16,840 --> 00:06:18,840 GENETICS BRANCH WHERE HIS MAIN 123 00:06:18,840 --> 00:06:21,280 ACTIVITY IS THE DEVELOPMENT AND 124 00:06:21,280 --> 00:06:25,920 APPLICATION OF NEXT-GENERATION 125 00:06:25,920 --> 00:06:28,880 SEQUENCING TO PROFILE SOME ADDED 126 00:06:28,880 --> 00:06:30,200 CHANGES DRIVING MULTIPLE TYPES 127 00:06:30,200 --> 00:06:35,440 OF PEDIATRIC SOLID TUMORS AND IN 128 00:06:35,440 --> 00:06:39,000 2018, HE BECAME AN NIH LASKER 129 00:06:39,000 --> 00:06:40,040 INVESTIGATOR IN THE PEDIATRIC 130 00:06:40,040 --> 00:06:43,280 ONCOLOGY BRANCH. 131 00:06:43,280 --> 00:06:46,440 WELL, LET US GET ON TO THIS 132 00:06:46,440 --> 00:06:48,520 EXCITING TOPIC WHICH I WOULD 133 00:06:48,520 --> 00:06:51,960 POINT OUT IF YOU LOOK IN BOOKS 134 00:06:51,960 --> 00:06:55,840 AS RECENTLY AS PERHAPS ONLY 135 00:06:55,840 --> 00:06:57,000 SEVEN, EIGHT OR NINE YEARS AGO, 136 00:06:57,000 --> 00:06:59,960 THESE DISEASES ARE MENTIONED AND 137 00:06:59,960 --> 00:07:02,440 DESCRIBED BUT USUALLY HAVE THE 138 00:07:02,440 --> 00:07:03,960 ADDITIONAL STATEMENT THAT ASIDE 139 00:07:03,960 --> 00:07:06,040 FROM SURGERY IN SOME CASES, NOT 140 00:07:06,040 --> 00:07:09,520 MUCH CAN BE DONE ABOUT THEM. 141 00:07:09,520 --> 00:07:11,760 WE'RE LIVING IN A DIFFERENT 142 00:07:11,760 --> 00:07:13,440 WORLD THANKS TO RESEARCH AND 143 00:07:13,440 --> 00:07:15,200 CLINICAL STUDIES THAT YOU'LL 144 00:07:15,200 --> 00:07:17,920 HEAR ABOUT NOW. 145 00:07:17,920 --> 00:07:19,600 SO, BRIGITTE, PLEASE. 146 00:07:19,600 --> 00:07:22,040 >> THANK YOU, DR. ARIAS. 147 00:07:22,040 --> 00:07:25,320 JACK AND I BOTH APPRECIATE THE 148 00:07:25,320 --> 00:07:27,760 OPPORTUNITY TO SPEAK TODAY. 149 00:07:27,760 --> 00:07:29,680 I WANT TO UP FRONT 150 00:07:29,680 --> 00:07:31,600 THANK MY PATIENT HEATHER AND ALL 151 00:07:31,600 --> 00:07:34,920 OF THE PATIENTS WHO HAVE 152 00:07:34,920 --> 00:07:35,560 PARTICIPATED IN THE RESEARCH 153 00:07:35,560 --> 00:07:37,400 THAT WE'RE PRESENTING TODAY 154 00:07:37,400 --> 00:07:38,640 BECAUSE WITHOUT THEM NO PROGRESS 155 00:07:38,640 --> 00:07:39,560 WOULD HAVE BEEN MADE. 156 00:07:39,560 --> 00:07:41,200 THE TOPIC WILL BE ON 157 00:07:41,200 --> 00:07:42,280 NEUROFIBROMATOSIS TYPE-1. 158 00:07:42,280 --> 00:07:46,720 WE HAVE NO FINANCIAL 159 00:07:46,720 --> 00:07:50,000 DISCLOSURES, DR. SHERN AND I BUT 160 00:07:50,000 --> 00:07:58,320 I WILL SPEAK OF 161 00:07:58,320 --> 00:07:59,480 INVESTIGATIONAL APPROACHES AND 162 00:07:59,480 --> 00:08:05,280 WE'LL TALK ABOUT THE NATURAL 163 00:08:05,280 --> 00:08:14,200 HISTORY OF TUMORS THAT DEVELOP 164 00:08:14,200 --> 00:08:24,400 IN NF 1 AND TALK ABOUT THE 165 00:08:24,400 --> 00:08:27,880 DEVELOPMENT OF EFFECTIVE 166 00:08:27,880 --> 00:08:31,800 TREATMENTS FOR NEUROFIBROMATOSIS 167 00:08:31,800 --> 00:08:34,680 OR NF 1 RELATED TUMORS AND WE'LL 168 00:08:34,680 --> 00:08:37,440 TALK ABOUT THE TUMOR 169 00:08:37,440 --> 00:08:38,600 MICROENVIRONMENT AND ITS 170 00:08:38,600 --> 00:08:41,480 IMPORTANCE IN NF 1 AND TOOLS 171 00:08:41,480 --> 00:08:46,200 HE'S USING TO DEFINE TUMOR 172 00:08:46,200 --> 00:08:47,800 HETEROGENEITY TO MALIGNANT AND 173 00:08:47,800 --> 00:08:50,000 THE STRATEGIES WE'RE DEVELOPING 174 00:08:50,000 --> 00:08:53,000 TO MANAGE NF 1 PATIENTS AT RISK 175 00:08:53,000 --> 00:08:55,360 FOR MALIGNANT TRANSFORMATION. 176 00:08:55,360 --> 00:08:58,400 WE'RE THRILLED TO BE WORKING AT 177 00:08:58,400 --> 00:09:00,280 THE NIH CLINICAL CENTER AND AT 178 00:09:00,280 --> 00:09:01,760 THE NCI. 179 00:09:01,760 --> 00:09:04,400 IN MY MIND IT'S THE BEST PLACE 180 00:09:04,400 --> 00:09:05,480 EVER TO CONDUCT CLINICAL 181 00:09:05,480 --> 00:09:07,720 RESEARCH AND I DO WANT TO THANK 182 00:09:07,720 --> 00:09:09,040 EVERYONE WHO PROVIDES THE 183 00:09:09,040 --> 00:09:14,000 AMAZING RESOURCES AT THE NIH BUT 184 00:09:14,000 --> 00:09:16,800 ALSO WITHIN THE NCI AND YOU SEE 185 00:09:16,800 --> 00:09:18,960 THE PEDIATRIC ONCOLOGY BRANCH. 186 00:09:18,960 --> 00:09:20,240 WE'RE A HIGHLY COLLABORATIVE 187 00:09:20,240 --> 00:09:22,600 GROUP AND A WANT TO THANK ALL OF 188 00:09:22,600 --> 00:09:26,000 OUR MEMBERS IN THE PEDIATRIC 189 00:09:26,000 --> 00:09:27,480 ONCOLOGY BRANCH FOR THEIR 190 00:09:27,480 --> 00:09:27,800 COMMITMENT. 191 00:09:27,800 --> 00:09:31,800 I'M STARTING WITH AN OVERVIEW OF 192 00:09:31,800 --> 00:09:33,040 NF 1. 193 00:09:33,040 --> 00:09:35,760 IT'S A FAIRLY COMMON SINGLE-GENE 194 00:09:35,760 --> 00:09:39,000 DISORDER CAUSED BY A MUTATION IN 195 00:09:39,000 --> 00:09:41,680 THE NF 1 GENE AND OCCURS IN 196 00:09:41,680 --> 00:09:46,720 ABOUT 1 IN 5,000 PEOPLE AND 197 00:09:46,720 --> 00:09:48,600 INHERITED IN AN AUTOSOMIC 198 00:09:48,600 --> 00:09:49,240 DOMINANT FASHION. 199 00:09:49,240 --> 00:09:51,120 IT MEANS IF YOU HAVE A MOM OR 200 00:09:51,120 --> 00:09:53,400 DAD AND INHERIT IT THE CHANCES 201 00:09:53,400 --> 00:09:58,760 YOU'LL HAVE IT IS ABOUT 50%. 202 00:09:58,760 --> 00:10:05,000 THE NF 1 GENE PRODUCT NEURAL 203 00:10:05,000 --> 00:10:06,600 FIBROMIN CAN CONTROL THE RAS 204 00:10:06,600 --> 00:10:07,560 PATHWAY. 205 00:10:07,560 --> 00:10:10,400 IT'S MUTATED IN MANY TYPES OF 206 00:10:10,400 --> 00:10:10,760 CANCERS. 207 00:10:10,760 --> 00:10:15,200 I'LL TALK MORE ABOUT THIS BUT 208 00:10:15,200 --> 00:10:21,200 WHEN NF 1 MANIFESTS IT LEADS TO 209 00:10:21,200 --> 00:10:25,000 UPREGULATION AND IT'S VERY 210 00:10:25,000 --> 00:10:27,000 CHARACTERISTIC CUTANEOUS 211 00:10:27,000 --> 00:10:28,640 FINDINGS SUCH AS COFFEE-COLORED 212 00:10:28,640 --> 00:10:30,920 SPOTS ON THE SKIN. 213 00:10:30,920 --> 00:10:32,840 CUTANEOUS NEURAL FIBROMAS YOU'LL 214 00:10:32,840 --> 00:10:36,200 SEE ON THE RIGHT SIDE AND A 215 00:10:36,200 --> 00:10:43,840 FRECKLING IN THE AUXILLA AND MY 216 00:10:43,840 --> 00:10:48,880 EFFORTS HAVE BEEN FOCUSSING ON 217 00:10:48,880 --> 00:10:49,880 TUMORS WITH NF 1 DEVELOPED AND 218 00:10:49,880 --> 00:10:51,880 MY FOCUS HAS BEEN ON TUMORS AS 219 00:10:51,880 --> 00:10:58,000 DR. ARIAS ALLUDED TO THAT ARISE 220 00:10:58,000 --> 00:11:02,440 IN NERVES, ATYPICAL TUMORS IN 221 00:11:02,440 --> 00:11:04,440 SHORT AND NPNST. 222 00:11:04,440 --> 00:11:06,600 WHEN I START THE WORK A LONG 223 00:11:06,600 --> 00:11:09,320 TIME THERE WERE NO EFFECTIVE 224 00:11:09,320 --> 00:11:12,200 MEDICAL TREATMENTS FOR MOST THE 225 00:11:12,200 --> 00:11:12,440 TUMORS. 226 00:11:12,440 --> 00:11:14,680 NF 1 CAN BE CLINICALLY DIAGNOSED 227 00:11:14,680 --> 00:11:16,560 IN THE VAST MAJORITY OF PATIENTS 228 00:11:16,560 --> 00:11:19,240 BY THE AGE OF SIX YEARS. 229 00:11:19,240 --> 00:11:24,480 THE TYPICAL FINDINGS ARE 230 00:11:24,480 --> 00:11:28,040 FRECKLING, NEURAL FIBROMAS AND 231 00:11:28,040 --> 00:11:29,320 THE DIAGNOSTIC CRITERIA DEVELOP 232 00:11:29,320 --> 00:11:30,840 DEPENDING ON WHETHER HAVE YOU A 233 00:11:30,840 --> 00:11:32,720 PARENT WITH NF 1 OR DON'T. 234 00:11:32,720 --> 00:11:34,240 IF YOU HAVE A PARENT WITH NF 1 235 00:11:34,240 --> 00:11:38,000 YOU ONLY HAVE TO MEET ONE OF THE 236 00:11:38,000 --> 00:11:40,640 OTHER CRITERIA LISTED HERE. 237 00:11:40,640 --> 00:11:41,800 IF YOU DON'T HAVE A PARENT WITH 238 00:11:41,800 --> 00:11:46,040 NF 1 YOU'LL HAVE TO MEET TWO 239 00:11:46,040 --> 00:11:46,320 CRITERIA. 240 00:11:46,320 --> 00:11:50,040 THE MOST TYPICAL ONES ARE THE 241 00:11:50,040 --> 00:12:00,320 CAFE AU LAIT MATCHES. 242 00:12:00,320 --> 00:12:05,320 IT'S INTERESTING THERE'S VERY 243 00:12:05,320 --> 00:12:06,800 FEW PHENOTYPE, GENOTYPE 244 00:12:06,800 --> 00:12:10,920 MUTATIONS AND PREDICTS FOR THE 245 00:12:10,920 --> 00:12:12,400 CLINICAL BEHAVIOR. 246 00:12:12,400 --> 00:12:17,400 IN A FAMILY THE CLINICAL 247 00:12:17,400 --> 00:12:19,200 MANIFESTATIONS CAN BE HIGHLY 248 00:12:19,200 --> 00:12:19,840 VARIABLE. 249 00:12:19,840 --> 00:12:23,240 THERE'S ONE IMPORTANT 250 00:12:23,240 --> 00:12:23,880 GENOTYPE/PHENOTYPE CORRELATION 251 00:12:23,880 --> 00:12:26,000 WHEN HAVE YOU A LARGE DELETION 252 00:12:26,000 --> 00:12:27,800 OF THE NF 1 GENE THESE PATIENTS 253 00:12:27,800 --> 00:12:31,800 ARE AT INCREASED RISK FOR 254 00:12:31,800 --> 00:12:33,600 DEVELOPMENT OF AGGRESSIVE TUMORS 255 00:12:33,600 --> 00:12:42,880 CALLED MPNTS OR PERIPHERAL 256 00:12:42,880 --> 00:12:43,520 PERIPHERAL TUMORS. 257 00:12:43,520 --> 00:12:47,080 THEY DEVELOP OVER TIME AND IT'S 258 00:12:47,080 --> 00:12:48,720 IMPORTANT FROM A PATIENT 259 00:12:48,720 --> 00:12:50,200 PERSPECTIVE. 260 00:12:50,200 --> 00:12:52,920 IT DOESN'T MANIFEST AT ONE TIME 261 00:12:52,920 --> 00:12:55,680 POINT BUT THROUGHOUT LIFE AND 262 00:12:55,680 --> 00:12:59,840 THE RED ARROWS SOME 263 00:12:59,840 --> 00:13:02,000 MANIFESTATIONS DEVELOP EARLY 264 00:13:02,000 --> 00:13:07,800 SUCH AS THE CAFE AU LAIT NODULES 265 00:13:07,800 --> 00:13:10,520 AND MALIGNANT TUMORS BUT THERE 266 00:13:10,520 --> 00:13:14,000 ARE A FEW MANIFESTATIONS WE 267 00:13:14,000 --> 00:13:15,760 THINK ONLY DEVELOP DURING A 268 00:13:15,760 --> 00:13:18,440 SHORT PERIOD OF PEOPLE SUCH AS 269 00:13:18,440 --> 00:13:21,520 THE PLEXI FORM FIBROMAS OR THE 270 00:13:21,520 --> 00:13:22,920 CHANGE THAT WE DON'T BELIEVE 271 00:13:22,920 --> 00:13:23,800 HAPPEN LATER IN LIFE. 272 00:13:23,800 --> 00:13:25,920 WHAT THIS MEANS FOR A PATIENT 273 00:13:25,920 --> 00:13:29,000 WITH NF 1 IS THEY HAVE TO BE 274 00:13:29,000 --> 00:13:30,400 PREPARED TO SEE CHANGES 275 00:13:30,400 --> 00:13:33,120 THROUGHOUT THEIR LIFE AND NEED 276 00:13:33,120 --> 00:13:35,000 TO BE SEEN BY EXPERT DOCTORS FOR 277 00:13:35,000 --> 00:13:35,600 THIS REASON. 278 00:13:35,600 --> 00:13:41,800 I'M NOW FOCUSSING ON THE 279 00:13:41,800 --> 00:13:43,640 PERIPHERAL NERVE SHEATH TUMORS 280 00:13:43,640 --> 00:13:45,560 THIS INCLUDES CUTANEOUS TUMORS 281 00:13:45,560 --> 00:13:47,880 YOU SEE ON THE PICTURE AND HERE 282 00:13:47,880 --> 00:13:49,360 ON AN MRI. 283 00:13:49,360 --> 00:13:51,840 THE TUMORS ARE CHARACTERIZED BY 284 00:13:51,840 --> 00:14:02,200 LOSS OF THE SECOND NF 1 ALLELES 285 00:14:02,200 --> 00:14:04,840 THEY TYPICALLY DEVELOP DURING 286 00:14:04,840 --> 00:14:07,600 PUBERTY AND NOT BABIES OR YOUNG 287 00:14:07,600 --> 00:14:10,560 CHILDREN AND THERE'S PLEXI FORM 288 00:14:10,560 --> 00:14:10,880 NEUROFIBROMAS. 289 00:14:10,880 --> 00:14:14,640 THEY CAN BE LARGE AND TRAVEL 290 00:14:14,640 --> 00:14:16,880 ALONG NERVES AND BRANCHES AND 291 00:14:16,880 --> 00:14:21,320 CAN OCCUR ANYWHERE IN THE BODY 292 00:14:21,320 --> 00:14:23,840 AND CHARACTERIZED BY NF 1 AND 293 00:14:23,840 --> 00:14:27,800 THE WORSE IS THE MPNTS TUMORS 294 00:14:27,800 --> 00:14:30,720 THAT ARE VERY AGGRESSIVE TUMORS 295 00:14:30,720 --> 00:14:31,440 THAT ARE CHARACTERIZED BY 296 00:14:31,440 --> 00:14:34,720 ADDITIONAL GENOMIC CHANGES AND 297 00:14:34,720 --> 00:14:37,680 DR. SHERN WILL TALK ABOUT THIS. 298 00:14:37,680 --> 00:14:39,800 THESE TUMORS REQUIRE SURGICAL 299 00:14:39,800 --> 00:14:42,000 RESECTION, COMPLETE RESURGICAL 300 00:14:42,000 --> 00:14:43,480 RESECTION FOR CURE AND RECENTLY 301 00:14:43,480 --> 00:14:45,640 WE AND OTHERS HAVE DESCRIBED 302 00:14:45,640 --> 00:14:47,800 TUMORS THAT ARE BORDERLINE IN 303 00:14:47,800 --> 00:14:51,480 THEIR BIOLOGY CALLED ATYPICAL 304 00:14:51,480 --> 00:14:56,560 NEURAL FIBROMAS THAT HAVE THE 305 00:14:56,560 --> 00:14:58,080 CHARACTERISTIC APPEARANCE THAT 306 00:14:58,080 --> 00:15:00,000 HAVE ATYPICAL CELLS AND 307 00:15:00,000 --> 00:15:03,040 CHARACTERIZED BY AN ADDITIONAL 308 00:15:03,040 --> 00:15:06,040 CHANGE OF A GENE AND I'M NOW 309 00:15:06,040 --> 00:15:08,040 SWITCHING TO MY, HEATHER, WHO 310 00:15:08,040 --> 00:15:12,680 ACTUALLY HAS HAD ALL OF THESE 311 00:15:12,680 --> 00:15:14,440 TUMORS AT VARIOUS STAGES AND 312 00:15:14,440 --> 00:15:16,000 IT'S WONDERFUL HEATHER AGREED TO 313 00:15:16,000 --> 00:15:16,680 PARTICIPATE. 314 00:15:16,680 --> 00:15:20,120 I'LL UNSHARE MY SCREEN SO WE CAN 315 00:15:20,120 --> 00:15:22,200 SEE HEATHER AND I WILL ACTUALLY 316 00:15:22,200 --> 00:15:27,000 ASK HEATHER A FEW QUESTIONS 317 00:15:27,000 --> 00:15:28,160 ABOUT THE NEUROFIBROMATOSIS. 318 00:15:28,160 --> 00:15:29,760 HEATHER, THANK YOU VERY MUCH FOR 319 00:15:29,760 --> 00:15:30,240 JOINING TODAY. 320 00:15:30,240 --> 00:15:30,960 >> SURE. 321 00:15:30,960 --> 00:15:35,800 >> I KNOW YOU'RE BUSY AND WE 322 00:15:35,800 --> 00:15:42,560 REALLY DO APPRECIATE IT. 323 00:15:42,560 --> 00:15:44,080 PEOPLE WILL REMEMBER YOU AS 324 00:15:44,080 --> 00:15:47,480 DR. ARIAS SAID AND WHATEVER YOU 325 00:15:47,480 --> 00:15:49,400 SAY THEY WILL REMEMBER. 326 00:15:49,400 --> 00:15:51,240 MAYBE I CAN ASK IF YOU CAN TELL 327 00:15:51,240 --> 00:15:52,840 US HOW OLD YOU WERE WHEN YOU 328 00:15:52,840 --> 00:15:55,880 WERE DIAGNOSED AND DO YOU 329 00:15:55,880 --> 00:15:57,440 REMEMBER WHAT THE FINDINGS WERE 330 00:15:57,440 --> 00:15:58,800 WHEN YOU WERE DIAGNOSED? 331 00:15:58,800 --> 00:16:01,600 CAN YOU TALK ABOUT THAT A LITTLE 332 00:16:01,600 --> 00:16:02,040 BIT? 333 00:16:02,040 --> 00:16:06,400 >> SO I WAS FIRST DIAGNOSED WITH 334 00:16:06,400 --> 00:16:08,800 NEUROFIBROMATOSIS WHEN I WAS 9 335 00:16:08,800 --> 00:16:09,600 MONTHS OLD. 336 00:16:09,600 --> 00:16:12,120 I DON'T REMEMBER A WHOLE LOT 337 00:16:12,120 --> 00:16:13,400 OBVIOUSLY ABOUT THAT BECAUSE 338 00:16:13,400 --> 00:16:15,840 BASED OFF MY AGE BUT I DO HAVE 339 00:16:15,840 --> 00:16:18,000 SOME MEMORIES OF REMEMBERING 340 00:16:18,000 --> 00:16:20,800 WHEN I WAS ABOUT 6 YEARS OLD IS 341 00:16:20,800 --> 00:16:26,920 WHEN I STARTED HAVING THE ACTUAL 342 00:16:26,920 --> 00:16:28,400 NEUROFIBROMA NODULES OR LUMPS OR 343 00:16:28,400 --> 00:16:30,640 WHATEVER YOU WANT TO CALL THEM. 344 00:16:30,640 --> 00:16:31,840 AT THAT POINT THEY THOUGHT 345 00:16:31,840 --> 00:16:35,480 POSSIBLY I HAD LEUKEMIA WHEN 346 00:16:35,480 --> 00:16:37,440 THEY FIRST STARTED APPEARING. 347 00:16:37,440 --> 00:16:39,040 THAT HAVE SOME MEMORIES OF THAT 348 00:16:39,040 --> 00:16:40,560 WHEN I WAS AROUND 6. 349 00:16:40,560 --> 00:16:43,840 >> AND HEATHER, WHAT HAS BEEN 350 00:16:43,840 --> 00:16:45,920 YOUR EXPERIENCE GROWING UP WITH 351 00:16:45,920 --> 00:16:46,440 NF 1? 352 00:16:46,440 --> 00:16:50,040 I KNOW YOU'VE HAD QUITE A NUMBER 353 00:16:50,040 --> 00:16:51,880 OF COMPLICATIONS AND EVENTS. 354 00:16:51,880 --> 00:16:54,240 I DON'T FLOW IF YOU WANT TO TALK 355 00:16:54,240 --> 00:16:55,880 A LITTLE BIT ABOUT THIS BECAUSE 356 00:16:55,880 --> 00:16:58,920 IT'S ACTUALLY QUITE IMPRESSIVE. 357 00:16:58,920 --> 00:17:01,480 >> SO WHEN I WAS ABOUT 14 YEARS 358 00:17:01,480 --> 00:17:03,840 OLD I WOULD HAVE BEEN DIAGNOSED 359 00:17:03,840 --> 00:17:08,240 WITH MY FIRST MALIGNANT TUMOR 360 00:17:08,240 --> 00:17:11,000 AND THAT WAS IN MY CALF. 361 00:17:11,000 --> 00:17:13,800 I WAS 14 AND WAS IN NINTH GRADE 362 00:17:13,800 --> 00:17:15,280 AND HAVING A LOT OF PAIN IN MY 363 00:17:15,280 --> 00:17:17,800 FOOT AND ONE EVENING MY MOM WAS 364 00:17:17,800 --> 00:17:24,760 WITH ME AND COULD SEE AND LIKE 365 00:17:24,760 --> 00:17:27,320 SAW THERE WAS A LUMP THAT HAD 366 00:17:27,320 --> 00:17:27,560 CHANGED. 367 00:17:27,560 --> 00:17:29,400 AT THAT POINT SHE HAD GOTTEN IN 368 00:17:29,400 --> 00:17:31,360 CONTACT WITH ONE OF MY DOCTORS 369 00:17:31,360 --> 00:17:33,720 AND AT THAT TIME I WASN'T A 370 00:17:33,720 --> 00:17:35,440 PATIENT AT THE NIH YET. 371 00:17:35,440 --> 00:17:37,960 SO THAT ONE WOULD HAVE BEEN 372 00:17:37,960 --> 00:17:40,040 REMOVED AND I HAD RADIATION TO 373 00:17:40,040 --> 00:17:43,160 THAT AREA. 374 00:17:43,160 --> 00:17:44,800 THEN I WOULD HAVE BEEN DIAGNOSED 375 00:17:44,800 --> 00:17:47,800 WITH MY SECOND MALIGNANCY IN 376 00:17:47,800 --> 00:17:48,200 2005. 377 00:17:48,200 --> 00:17:49,800 AT THAT POINT MY DOCTORS WHO 378 00:17:49,800 --> 00:17:52,600 WERE LOCAL TO THE AREA THAT I 379 00:17:52,600 --> 00:17:54,840 LIVE IN REFERRED ME TO THE NIH. 380 00:17:54,840 --> 00:17:58,240 SO FROM THAT POINT ON I HAVE 381 00:17:58,240 --> 00:18:01,040 BEEN A PATIENT OF DR. WIDEMANN. 382 00:18:01,040 --> 00:18:03,800 SO IN 2005 I HAD THE SECOND 383 00:18:03,800 --> 00:18:06,480 MALIGNANCY AND I WOULD HAVE HAD 384 00:18:06,480 --> 00:18:09,440 BOTH RADIATION AND CHEMO AND 385 00:18:09,440 --> 00:18:11,160 THEN ALSO THAT WOULD HAVE BEEN 386 00:18:11,160 --> 00:18:14,000 SURGICALLY REMOVED AS WELL. 387 00:18:14,000 --> 00:18:18,280 AND THEN I'VE HAD SEVERAL OTHER 388 00:18:18,280 --> 00:18:20,600 ATYPICAL NEUROFIBROMAS REMOVED 389 00:18:20,600 --> 00:18:21,000 OVER THE YEARS. 390 00:18:21,000 --> 00:18:25,000 I GET SCANS REGULARLY AT THE 391 00:18:25,000 --> 00:18:25,480 NIH. 392 00:18:25,480 --> 00:18:28,600 AND SO AS THEY GROW AND CHANGE, 393 00:18:28,600 --> 00:18:30,600 DIFFERENT ONES ARE RECOMMENDED 394 00:18:30,600 --> 00:18:34,400 TO BE REMOVED AND THEN I 395 00:18:34,400 --> 00:18:36,480 RECENTLY HAD ONE -- ANOTHER ONE 396 00:18:36,480 --> 00:18:37,720 REMOVED LIKE A WEEK AND A HALF 397 00:18:37,720 --> 00:18:39,800 AGO AND WE JUST FOUND OUT THAT 398 00:18:39,800 --> 00:18:41,240 ONE IS MALIGNANT AS WELL. 399 00:18:41,240 --> 00:18:45,200 SO THEY WERE ABLE TO REMOVE THE 400 00:18:45,200 --> 00:18:46,800 WHOLE TUMOR. 401 00:18:46,800 --> 00:18:48,040 AND RADIATION IS WHAT'S GOING TO 402 00:18:48,040 --> 00:18:50,760 BE THE NEXT COURSE FOR THAT ONE. 403 00:18:50,760 --> 00:18:55,800 >> HEATHER, THIS IS REALLY VERY 404 00:18:55,800 --> 00:18:58,200 REMARKABLE OF A STORY. 405 00:18:58,200 --> 00:19:03,800 I FEEL WE'VE BEEN WALKING 406 00:19:03,800 --> 00:19:06,560 TOGETHER MORE OR LESS. 407 00:19:06,560 --> 00:19:08,360 WHAT CAN TELL US ABOUT WHAT IT 408 00:19:08,360 --> 00:19:10,800 MEANS TO GROW UP WITH SOMETHING 409 00:19:10,800 --> 00:19:13,320 YOU CAN HAVE SOMETHING ALL THE 410 00:19:13,320 --> 00:19:13,680 TIME. 411 00:19:13,680 --> 00:19:15,400 HOW DO YOU ADJUST AND GET ON 412 00:19:15,400 --> 00:19:16,320 WITH YOUR LIFE? 413 00:19:16,320 --> 00:19:19,560 I KNOW YOU'RE GOING ON WITH YOUR 414 00:19:19,560 --> 00:19:19,760 LIFE. 415 00:19:19,760 --> 00:19:21,320 MANY THINGS HAVE CHANGED FOR YOU 416 00:19:21,320 --> 00:19:25,960 OVER THE LAST FEW YEARS. 417 00:19:25,960 --> 00:19:28,240 I THINK SOMETHING FOR ME I'VE 418 00:19:28,240 --> 00:19:29,920 ALWAYS LEARNED TO DEAL WITH 419 00:19:29,920 --> 00:19:31,560 BECAUSE IT'S SOMETHING I'VE 420 00:19:31,560 --> 00:19:35,800 GROWN UP WITH AND SOMETHING I'VE 421 00:19:35,800 --> 00:19:37,400 ALWAYS HAD. 422 00:19:37,400 --> 00:19:42,000 I KNOW THERE'S THINGS TO BE 423 00:19:42,000 --> 00:19:43,320 WATCHFUL OF BUT SOMETHING I'VE 424 00:19:43,320 --> 00:19:45,200 ALWAYS LEARNED TO LIVE WITH AND 425 00:19:45,200 --> 00:19:47,480 NOT LET IT SLOW ME DOWN OR STOP 426 00:19:47,480 --> 00:19:47,800 ME. 427 00:19:47,800 --> 00:19:50,000 I HAVE A WONDERFUL SUPPORTIVE 428 00:19:50,000 --> 00:19:52,640 FAMILY TOO AND THAT'S BEEN HUGE. 429 00:19:52,640 --> 00:19:54,720 WE'RE PART OF A WONDERFUL 430 00:19:54,720 --> 00:19:55,840 SUPPORTIVE CHURCH AS WELL AND 431 00:19:55,840 --> 00:19:59,840 THAT'S BEEN HUGE TOO. 432 00:19:59,840 --> 00:20:03,840 >> I WOULD SAY YOU'VE BEEN A 433 00:20:03,840 --> 00:20:05,680 FANTASTIC JOB IN ALWAYS BEING 434 00:20:05,680 --> 00:20:07,480 AVAILABLE WHEN WE SAID WE NEED 435 00:20:07,480 --> 00:20:09,200 TO SCAN YOU AGAIN. 436 00:20:09,200 --> 00:20:14,640 I HAVE A SLIDE THAT SHOWS YOU'VE 437 00:20:14,640 --> 00:20:16,400 HAD QUITE A FEW. 438 00:20:16,400 --> 00:20:17,680 >> FOR SURE. 439 00:20:17,680 --> 00:20:21,280 >> HEATHER, WHAT IS SOMETHING 440 00:20:21,280 --> 00:20:23,800 YOU THINK WE SHOULD FOCUS ON AS 441 00:20:23,800 --> 00:20:24,120 RESEARCHERS? 442 00:20:24,120 --> 00:20:25,160 >> IT WOULD BE WONDERFUL IF 443 00:20:25,160 --> 00:20:29,160 THERE WAS A CURE FOR THESE 444 00:20:29,160 --> 00:20:31,080 MALIGNANT TUMORS THAT COULD KEEP 445 00:20:31,080 --> 00:20:33,600 THEM FROM TURNING MALIGNANT OR 446 00:20:33,600 --> 00:20:35,400 STOP THEM FROM GROWING. 447 00:20:35,400 --> 00:20:36,760 STOP THEM FROM OCCURRING IN THE 448 00:20:36,760 --> 00:20:40,800 FIRST PLACE. 449 00:20:40,800 --> 00:20:43,280 >> I HAVE TO SAY IF WE COULD 450 00:20:43,280 --> 00:20:47,920 MAKE ONE THING HAPPEN THAT'S THE 451 00:20:47,920 --> 00:20:48,800 TOP ON OUR LIST. 452 00:20:48,800 --> 00:20:50,720 WE WILL NOT STOP WORKING, I 453 00:20:50,720 --> 00:20:54,520 PROMISE THAT, HEATHER, FOR SURE. 454 00:20:54,520 --> 00:20:56,800 I ALSO KNOW YOU'VE HAD SOME 455 00:20:56,800 --> 00:20:58,120 RECENT CHANGES IN YOUR LIFE AND 456 00:20:58,120 --> 00:20:59,760 TO ME THAT IS INSPIRING. 457 00:20:59,760 --> 00:21:03,440 I WAS WONDERING IF YOU WOULD BE 458 00:21:03,440 --> 00:21:04,360 WILLING TO SHARE -- 459 00:21:04,360 --> 00:21:09,320 >> MY HUSBAND AND I HAVE BECOME 460 00:21:09,320 --> 00:21:10,920 FOSTER PARENTS TWO AND A HALF 461 00:21:10,920 --> 00:21:13,400 YEARS AGO WE STARTED THE JOURNEY 462 00:21:13,400 --> 00:21:15,800 TO BECOMING FOSTER PARENTS AND 463 00:21:15,800 --> 00:21:19,840 WERE BLESSED TO HAVE A 464 00:21:19,840 --> 00:21:22,120 4-MONTH-OLD LITTLE BOY PLACED IN 465 00:21:22,120 --> 00:21:22,520 OUR HOME. 466 00:21:22,520 --> 00:21:23,440 WE GOT HIM RIGHT BEFORE 467 00:21:23,440 --> 00:21:26,360 EVERYTHING WITH COVID STARTED 468 00:21:26,360 --> 00:21:27,800 AND THEN WE ARE IN THE PROCESS 469 00:21:27,800 --> 00:21:30,520 OF ADOPTING HIM. 470 00:21:30,520 --> 00:21:31,800 SO NEXT WEEK WE WILL BE ADOPTING 471 00:21:31,800 --> 00:21:33,880 HIM SO WE'RE REALLY EXCITED FOR 472 00:21:33,880 --> 00:21:34,240 THAT. 473 00:21:34,240 --> 00:21:38,000 HE'S BEEN A JOY AND A BLESSING 474 00:21:38,000 --> 00:21:39,200 AND KEEPS US BUSY. 475 00:21:39,200 --> 00:21:41,320 >> CONGRATULATIONS, HEATHER. 476 00:21:41,320 --> 00:21:42,960 WHATEVER WE DO WE'LL TRY TO MAKE 477 00:21:42,960 --> 00:21:46,720 SURE THAT YOU CAN GO ABOUT YOUR 478 00:21:46,720 --> 00:21:48,920 LIFE AS MUCH AS YOU CAN BUT 479 00:21:48,920 --> 00:21:51,680 WE'LL BE ON YOUR SIDE AIMING TO 480 00:21:51,680 --> 00:21:55,800 HELP WITH WHATEVER WE CAN TO 481 00:21:55,800 --> 00:21:57,360 KEEP THINGS UNDER CONTROL AND I 482 00:21:57,360 --> 00:22:02,000 WONDER IF THERE IS TIME NOW FOR 483 00:22:02,000 --> 00:22:05,200 SOME QUESTIONS IN THE AUDIENCE? 484 00:22:05,200 --> 00:22:07,400 >> YES, LET'S SEE. 485 00:22:07,400 --> 00:22:09,760 HEATHER, LISTEN, THANK YOU FIRST 486 00:22:09,760 --> 00:22:11,600 OF ALL, ENORMOUSLY FOR TAKING 487 00:22:11,600 --> 00:22:13,560 THE TIME AND PARTICULARLY WHEN 488 00:22:13,560 --> 00:22:15,800 YOU HAVE AN INFANT YOU HAVE TO 489 00:22:15,800 --> 00:22:19,840 TAKE CARE OF. 490 00:22:19,840 --> 00:22:22,320 BUT ARE THERE OTHER PEOPLE IN 491 00:22:22,320 --> 00:22:24,400 YOUR FAMILY WHO HAVE DISEASES 492 00:22:24,400 --> 00:22:26,400 LIKE THIS? 493 00:22:26,400 --> 00:22:30,000 >> SO MY DAD -- WE WOULD HAVE 494 00:22:30,000 --> 00:22:34,560 FOUND OUT SIX MONTHS BEFORE HE 495 00:22:34,560 --> 00:22:37,960 PASSED AWAY THAT HE AS WELL HAD 496 00:22:37,960 --> 00:22:38,360 NEUROFIBROMATOSIS. 497 00:22:38,360 --> 00:22:41,400 WHEN I FIRST WOULD HAVE BEEN 498 00:22:41,400 --> 00:22:43,640 DIAGNOSED MY PARENTS WOULD HAVE 499 00:22:43,640 --> 00:22:45,720 HAD SOME AMOUNT OF TESTING OR 500 00:22:45,720 --> 00:22:47,400 LOOKED INTO SOME EXTENT IF 501 00:22:47,400 --> 00:22:48,920 EITHER HAD IT AND AT THAT TIME 502 00:22:48,920 --> 00:22:50,000 THEY WERE TOLD THEY WERE BOTH 503 00:22:50,000 --> 00:22:51,840 FINE. 504 00:22:51,840 --> 00:22:56,000 SO I HAVE AN OLDER SISTER WHO 505 00:22:56,000 --> 00:22:56,760 DOESN'T HAVE NEUROFIBROMATOSIS 506 00:22:56,760 --> 00:23:00,680 AND THEN IT WOULD BE ME AND MY 507 00:23:00,680 --> 00:23:05,680 NEXT BROTHER DOESN'T HAVE IT 508 00:23:05,680 --> 00:23:07,320 EITHER BUT MY YOUNGER BROTHER 509 00:23:07,320 --> 00:23:11,360 NEUROFIBROMATOSIS AND HE HAS 510 00:23:11,360 --> 00:23:12,600 PASSED AWAY TOO. 511 00:23:12,600 --> 00:23:15,760 WHETHER IT WAS UNCLEAR HIS 512 00:23:15,760 --> 00:23:18,520 MALIGNANCY WAS RELATED TO THE 513 00:23:18,520 --> 00:23:20,120 NEUROFIBROMA OR RELATED TO 514 00:23:20,120 --> 00:23:21,120 SOMETHING DIFFERENT, EVERYTHING 515 00:23:21,120 --> 00:23:23,400 WENT VERY QUICKLY WITH MY 516 00:23:23,400 --> 00:23:24,000 BROTHER AND HIS SICKNESS AND 517 00:23:24,000 --> 00:23:31,480 PASSING. 518 00:23:31,480 --> 00:23:34,680 SO BOTH FAMILY MEMBERS THAT HAD 519 00:23:34,680 --> 00:23:39,080 NEUROFIBROMATOSIS HAVE PASSED 520 00:23:39,080 --> 00:23:39,280 AWAY. 521 00:23:39,280 --> 00:23:42,000 MY DAD'S WASN'T RELATED AND MY 522 00:23:42,000 --> 00:23:43,400 BROTHER'S MAY OR MAY NOT HAVE 523 00:23:43,400 --> 00:23:43,720 BEEN. 524 00:23:43,720 --> 00:23:46,320 >> ONE OF OUR ATTENDEES WAS 525 00:23:46,320 --> 00:23:49,440 CURIOUS WHETHER YOUR DISEASE HAS 526 00:23:49,440 --> 00:23:52,640 BEEN ASSOCIATED WITH PAIN AND IF 527 00:23:52,640 --> 00:23:53,800 SO IS PAIN MANAGEMENT BEEN 528 00:23:53,800 --> 00:23:56,600 EFFECTIVE FOR YOU? 529 00:23:56,600 --> 00:24:00,000 >> SO TYPICALLY FOR ME THE ONLY 530 00:24:00,000 --> 00:24:03,760 TIME I'VE HAD AT LEAST ANY 531 00:24:03,760 --> 00:24:04,400 CONSISTENT PAIN HAS BEEN WITH 532 00:24:04,400 --> 00:24:08,400 THE MALIGNANCIES. 533 00:24:08,400 --> 00:24:10,400 AND THE THIRD ONE THEY REMOVED I 534 00:24:10,400 --> 00:24:11,760 WOULDN'T SAY I'VE HAD A GREAT 535 00:24:11,760 --> 00:24:15,600 DEAL OF PAIN WITH THAT ONE. 536 00:24:15,600 --> 00:24:19,840 NOT ANYTHING CONSISTENT SO WITH 537 00:24:19,840 --> 00:24:21,600 THE MALIGNANCIES I'VE HAD PAIN 538 00:24:21,600 --> 00:24:23,320 BUT OTHER THAN THAT I HAVEN'T. 539 00:24:23,320 --> 00:24:27,040 >> AND THERE'S ANOTHER QUESTION 540 00:24:27,040 --> 00:24:33,560 IN WHICH -- HOW DID IT HAPPEN 541 00:24:33,560 --> 00:24:38,000 THAT THE DIAGNOSIS -- WHEN WAS 542 00:24:38,000 --> 00:24:40,920 IT MADE AND WAS IT A 543 00:24:40,920 --> 00:24:44,880 PEDIATRICIAN WHO MADE THE 544 00:24:44,880 --> 00:24:47,680 DIAGNOSIS WERE YOU CHASING 545 00:24:47,680 --> 00:24:49,320 AROUND TRYING TO FIGURE IT OUT 546 00:24:49,320 --> 00:24:51,800 AND HOW DID IT UNFOLD? 547 00:24:51,800 --> 00:24:54,120 >> THE DIAGNOSIS WAS MADE AT 9 548 00:24:54,120 --> 00:24:57,000 MONTHS OLD AND MY MOM STARTED TO 549 00:24:57,000 --> 00:24:58,200 NOTICING DIFFERENT CHANGES ON MY 550 00:24:58,200 --> 00:25:00,400 SKIN AND HAD TAKEN ME TO THE 551 00:25:00,400 --> 00:25:01,800 DOCTORATE THAT POINT AND FROM 552 00:25:01,800 --> 00:25:03,840 THERE WE WERE SENT TO A 553 00:25:03,840 --> 00:25:08,160 SPECIALIST AT A LOCAL CHILDREN'S 554 00:25:08,160 --> 00:25:16,800 HOSPITAL. 555 00:25:16,800 --> 00:25:18,480 >> I DON'T SEE ANY MORE 556 00:25:18,480 --> 00:25:19,720 QUESTIONS SO THANK YOU VERY MUCH 557 00:25:19,720 --> 00:25:20,960 FOR TAKING THE TIME TO DO THIS 558 00:25:20,960 --> 00:25:23,400 AND WE WISH YOU AND YOUR FAMILY 559 00:25:23,400 --> 00:25:24,640 THE VERY BEST. 560 00:25:24,640 --> 00:25:26,400 WE'RE GLAD YOU'RE IN SUCH GOOD 561 00:25:26,400 --> 00:25:26,760 HANDS. 562 00:25:26,760 --> 00:25:27,800 >> THANK YOU. 563 00:25:27,800 --> 00:25:29,600 >> THANK YOU, HEATHER. 564 00:25:29,600 --> 00:25:29,920 THANKS A LOT. 565 00:25:29,920 --> 00:25:37,960 I'LL SHARE MY SCREEN AGAIN. 566 00:25:37,960 --> 00:25:39,800 AND LET ME KNOW IF YOU SEE THE 567 00:25:39,800 --> 00:25:43,280 SLIDES OKAY, I HOPE. 568 00:25:43,280 --> 00:25:49,000 SO FROM HERE I'LL MOVE ON TO 569 00:25:49,000 --> 00:25:50,880 TALK A LITTLE BIT ABOUT HEATHER 570 00:25:50,880 --> 00:25:53,160 AND NOW A 35-YEAR-OLD. 571 00:25:53,160 --> 00:25:58,760 AS HEATHER MENTIONED THIS IS 572 00:25:58,760 --> 00:26:00,840 INTERESTING, HER DAD HAD NF 1 573 00:26:00,840 --> 00:26:03,440 BUT NOT DIAGNOSED UNTIL LATER. 574 00:26:03,440 --> 00:26:05,880 WE HAVE SEEN THIS BEFORE BECAUSE 575 00:26:05,880 --> 00:26:06,960 MANIFESTATIONS CAN BE FAIRLY 576 00:26:06,960 --> 00:26:08,480 SUBTLE AND WHEN YOU LOOK AT 577 00:26:08,480 --> 00:26:10,200 HEATHER YOU WOULDN'T NECESSARILY 578 00:26:10,200 --> 00:26:15,800 THINK AT ALL HEATHER HAS 579 00:26:15,800 --> 00:26:18,280 NEUROFIBROMATOSIS TYPE-1 WITH 580 00:26:18,280 --> 00:26:23,400 HER SITTING THERE BUT HER FATHER 581 00:26:23,400 --> 00:26:27,840 HAT ULCERATIVE COLITIS AND SO 582 00:26:27,840 --> 00:26:31,720 DOES HEATHER WHICH IS AN 583 00:26:31,720 --> 00:26:33,680 INTRIGUING FINDING AND HER 584 00:26:33,680 --> 00:26:37,240 BROTHER DEVELOPED AN AGGRESSIVE 585 00:26:37,240 --> 00:26:41,720 MALIGNANCY THAT WAS A RARE 586 00:26:41,720 --> 00:26:43,880 SARCOMA TYPE OF TUMOR WE COULD 587 00:26:43,880 --> 00:26:54,480 NOT CHARACTERIZE VERY CLEARLY. 588 00:26:54,480 --> 00:26:55,600 HEATHER WAS DIAGNOSED BECAUSE OF 589 00:26:55,600 --> 00:26:59,480 THE SKIN FINDINGS AND SOMETHING 590 00:26:59,480 --> 00:27:00,600 FOR PEDIATRICIANS TO LOOK OUT 591 00:27:00,600 --> 00:27:05,760 FOR AND HAD HER FIRST LOW-GRADE 592 00:27:05,760 --> 00:27:10,600 MALIGNANCY IN 2001. 593 00:27:10,600 --> 00:27:20,520 SHE HAD A COLECTOMY AND IF 594 00:27:20,520 --> 00:27:22,440 PATIENTS HAVE NEW PAIN, PAIN 595 00:27:22,440 --> 00:27:24,160 THAT WAKES THEM UP AT NIGHT, 596 00:27:24,160 --> 00:27:27,520 PAIN THAT IS SEVERE, WE ARE ARE 597 00:27:27,520 --> 00:27:29,960 ALWAYS CONCERNED IT MAY BE A 598 00:27:29,960 --> 00:27:31,080 MALIGNANT TUMOR THOUGH OTHER 599 00:27:31,080 --> 00:27:34,720 TYPES OF TUMORS CAN CAUSE PAIN. 600 00:27:34,720 --> 00:27:38,000 AND THEN HEATHER CAME TO THE NIH 601 00:27:38,000 --> 00:27:43,800 TO ENROLL IN OUR NF 1 NATURAL 602 00:27:43,800 --> 00:27:46,000 HISTORY STUDY AND UNDERWENT 603 00:27:46,000 --> 00:27:46,720 RECESSIONS THREE TIMES OF 604 00:27:46,720 --> 00:27:48,440 DIFFERENT TYPES OF TUMORS WE 605 00:27:48,440 --> 00:27:49,480 WERE CONCERNED ABOUT. 606 00:27:49,480 --> 00:27:51,800 KNOWLEDGE OF THE TUMORS WERE 607 00:27:51,800 --> 00:27:54,560 CANCER TUMORS BUT VERY RECENTLY 608 00:27:54,560 --> 00:27:57,640 AS HEATHER MENTIONED JUST A FEW 609 00:27:57,640 --> 00:27:59,600 WEEKS AGO THERE WAS A LESION WE 610 00:27:59,600 --> 00:28:02,000 FOUND THAT WAS CONCERNING AND 611 00:28:02,000 --> 00:28:06,160 FOUND TO BE AN MPNST. 612 00:28:06,160 --> 00:28:07,520 >> CAN YOU SWITCH TO 613 00:28:07,520 --> 00:28:08,600 PRESENTATION MODE? 614 00:28:08,600 --> 00:28:09,960 WE CAN SEE YOUR ADDITIONAL 615 00:28:09,960 --> 00:28:10,200 SLIDES. 616 00:28:10,200 --> 00:28:17,680 >> OKAY, OF COURSE. 617 00:28:17,680 --> 00:28:18,520 IS THIS BETTER? 618 00:28:18,520 --> 00:28:18,880 DOES THIS WORK? 619 00:28:18,880 --> 00:28:22,520 >> ONE SECOND. 620 00:28:22,520 --> 00:28:26,720 CAN YOU SELECT IT AGAIN, PLEASE? 621 00:28:26,720 --> 00:28:28,120 >> I SWAPPED THE SCREEN. 622 00:28:28,120 --> 00:28:31,800 CAN YOU SEE THE SLIDES OKAY NOW 623 00:28:31,800 --> 00:28:35,280 OR IS THIS BETTER? 624 00:28:35,280 --> 00:28:39,320 WE'RE SEEING MULTIPLE SLIDES. 625 00:28:39,320 --> 00:28:43,960 PLEASE STOP SHARING AND COME 626 00:28:43,960 --> 00:28:44,160 BACK. 627 00:28:44,160 --> 00:28:52,200 >> OKAY. 628 00:28:52,200 --> 00:28:53,160 IS THIS BETTER? 629 00:28:53,160 --> 00:28:53,760 SELECT THE PRESENTATION MODE 630 00:28:53,760 --> 00:28:59,200 AGAIN. 631 00:28:59,200 --> 00:29:00,800 IS THIS BETTER? 632 00:29:00,800 --> 00:29:03,440 SORRY ABOUT THAT. 633 00:29:03,440 --> 00:29:06,040 I'M SHOWING YOU HERE A PET SCAN 634 00:29:06,040 --> 00:29:09,960 WHICH IS A NUCLEAR MEDICINE TEST 635 00:29:09,960 --> 00:29:11,880 WHERE LABELLED SUGAR IS INJECTED 636 00:29:11,880 --> 00:29:13,760 INTO THE VEIN AND THEY GO 637 00:29:13,760 --> 00:29:17,640 ANYWHERE IN THE BODY WHERE 638 00:29:17,640 --> 00:29:19,800 NUTRITION IS NEEDED THAT 639 00:29:19,800 --> 00:29:22,880 INCLUDES INFECTIONS, FOR 640 00:29:22,880 --> 00:29:24,480 EXAMPLE, OR TUMORS AND 641 00:29:24,480 --> 00:29:26,560 HIGHLIGHTING HERE IN RED ARROW 642 00:29:26,560 --> 00:29:28,240 AN AREA THAT IS DARK WHICH MEANS 643 00:29:28,240 --> 00:29:32,720 THE SUGAR OR DYE IS ACCUMULATING 644 00:29:32,720 --> 00:29:33,360 IN THE PELVIC AREA. 645 00:29:33,360 --> 00:29:35,080 THIS IS THE TORSO AND RIGHT LEG 646 00:29:35,080 --> 00:29:37,760 AND LEFT LEG. 647 00:29:37,760 --> 00:29:39,120 THEN YOU SEE ON THE SCREEN THE 648 00:29:39,120 --> 00:29:41,080 PELVIS AND YOU SEE THE RIGHT LEG 649 00:29:41,080 --> 00:29:43,440 AND LEFT LEG. 650 00:29:43,440 --> 00:29:47,240 IN WHITE YOU SEE NEUROFIBROMAS 651 00:29:47,240 --> 00:29:50,600 IN HEATHER'S BODY AND A ROUND 652 00:29:50,600 --> 00:29:52,720 APPEARING TUMOR LESION THAT 653 00:29:52,720 --> 00:29:55,280 RESPONDS TO THE DARK AREA ON THE 654 00:29:55,280 --> 00:29:57,600 PET SCAN WHICH MEANS AN AREA OF 655 00:29:57,600 --> 00:30:02,000 CONCERN FOR US AND THIS WAS 656 00:30:02,000 --> 00:30:06,480 ACTUALLY HER FIRST MALIGNANT 657 00:30:06,480 --> 00:30:10,200 TUMOR AND DO YOU SEE MY ARROW 658 00:30:10,200 --> 00:30:10,400 OKAY? 659 00:30:10,400 --> 00:30:13,280 YOU SEE THE TUMOR ON THE AXIAL 660 00:30:13,280 --> 00:30:15,520 IMAGE. 661 00:30:15,520 --> 00:30:17,200 IN ADDITION YOU SEE OTHER AREAS 662 00:30:17,200 --> 00:30:20,480 ON THE PET SCAN CIRCLED IN 663 00:30:20,480 --> 00:30:22,280 BLACK, WHICH ARE AREAS OF 664 00:30:22,280 --> 00:30:24,880 INCREASE UPTAKE BUT NOT NEARLY 665 00:30:24,880 --> 00:30:28,760 AS MUCH AS WE SAW IN THE 666 00:30:28,760 --> 00:30:31,000 MALIGNANT PERIPHERAL TUMOR. 667 00:30:31,000 --> 00:30:32,600 HEATHER THEN JOINED US FOR THE 668 00:30:32,600 --> 00:30:33,720 NATURAL HISTORY STUDY. 669 00:30:33,720 --> 00:30:35,720 ON THE RIGHT YOU SEE HER AGE AND 670 00:30:35,720 --> 00:30:37,240 YOU SEE THE VOLUME OF EACH OF 671 00:30:37,240 --> 00:30:43,600 THE INDIVIDUAL TUMORS ON THE Y 672 00:30:43,600 --> 00:30:43,840 AXIS. 673 00:30:43,840 --> 00:30:47,240 ESSENTIALLY EVERY DARK SPOT IS 674 00:30:47,240 --> 00:30:48,920 AN MRI FROM THE NIH CLINICAL 675 00:30:48,920 --> 00:30:49,160 CENTER. 676 00:30:49,160 --> 00:30:51,200 YOU CAN SEE ON THE RIGHT MOST 677 00:30:51,200 --> 00:30:53,000 HER TUMORS GREW OVER TIME. 678 00:30:53,000 --> 00:30:54,800 THERE'S ONLY ONE IN LIGHT GREEN 679 00:30:54,800 --> 00:30:58,960 THAT ACTUALLY HAD SOME DECREASE 680 00:30:58,960 --> 00:30:59,400 IN VOLUME OVER TIME. 681 00:30:59,400 --> 00:31:03,720 ON THE PET SCAN ON THE LEFT YOU 682 00:31:03,720 --> 00:31:05,280 SEE A NUMBER OF AREAS OF 683 00:31:05,280 --> 00:31:06,200 INCREASED UPTAKE. 684 00:31:06,200 --> 00:31:08,600 THESE ARE THE LESIONS WE MONITOR 685 00:31:08,600 --> 00:31:10,920 FOR GROWTH, FOR PAIN AND FOR 686 00:31:10,920 --> 00:31:14,600 UPTAKE ON THE PET SCAN TO MAKE 687 00:31:14,600 --> 00:31:16,280 SURE THAT WE CAPTURE THEM BEFORE 688 00:31:16,280 --> 00:31:19,120 THEY BECOME MALIGNANT AND THEN 689 00:31:19,120 --> 00:31:23,280 IN THE MIDDLE YOU SEE AN MRI 690 00:31:23,280 --> 00:31:27,560 PICTURE WE CALL IT A CORONAL 691 00:31:27,560 --> 00:31:30,640 PLANE AND ARM, BODY AND LEGS AND 692 00:31:30,640 --> 00:31:32,400 THEN YOU SEE THE NODULE LESION 693 00:31:32,400 --> 00:31:35,000 THIS IS AGAIN ONE OF THE TUMORS 694 00:31:35,000 --> 00:31:38,080 THAT WE RESECTED AND WAS NOT 695 00:31:38,080 --> 00:31:39,800 MALIGNANT. 696 00:31:39,800 --> 00:31:42,920 HERE YOU SEE THE MOST RECENT 697 00:31:42,920 --> 00:31:44,040 EVOLVEMENT IN HEATHER WHERE ON 698 00:31:44,040 --> 00:31:47,200 THE LOWER PANEL YOU SEE IMAGING 699 00:31:47,200 --> 00:31:49,560 STUDIES FROM 2019 AND ON THE 700 00:31:49,560 --> 00:31:52,680 UPPER PANEL YOU SEE IMAGING 701 00:31:52,680 --> 00:31:54,920 STUDIES FROM 2022 AND THE LEFT 702 00:31:54,920 --> 00:31:58,200 PANEL YOU SEE WITH RED ARROW A 703 00:31:58,200 --> 00:31:59,840 SMALL LESION JUST IN THE AREA OF 704 00:31:59,840 --> 00:32:04,360 WHETHER THE CAPULA ON THE LEFT 705 00:32:04,360 --> 00:32:07,600 AND IN 2019 WHEN YOU GO TO THE 706 00:32:07,600 --> 00:32:08,760 UPPER PANEL IT'S CLEARLY 707 00:32:08,760 --> 00:32:09,640 INCREASED IN SIZE. 708 00:32:09,640 --> 00:32:11,800 AND IF YOU LOOK ON THE RIGHT 709 00:32:11,800 --> 00:32:14,760 PANEL AND THIS IS THE PET SCAN 710 00:32:14,760 --> 00:32:18,000 WHERE AGAIN IN 2019 YOU SEE A 711 00:32:18,000 --> 00:32:19,240 SMALLER LESION THAT'S BRIGHT. 712 00:32:19,240 --> 00:32:22,440 THIS HAS INCREASED QUITE A BIT 713 00:32:22,440 --> 00:32:24,200 ON THE MOST RECENT IMAGING 714 00:32:24,200 --> 00:32:25,400 STUDIES AND WHAT RAISED THE 715 00:32:25,400 --> 00:32:27,600 CONCERN FOR US THAT THIS MIGHT 716 00:32:27,600 --> 00:32:35,680 BE A MALIGNANT TUMOR AND WE 717 00:32:35,680 --> 00:32:39,800 PERFORM BIOPSIES AND IT WAS A 718 00:32:39,800 --> 00:32:42,200 PERIPHERAL TUMOR AND HEATHER 719 00:32:42,200 --> 00:32:43,840 WILL UNDER GO ADDITIONAL 720 00:32:43,840 --> 00:32:45,680 TREATMENT WITH IMAGING AND 721 00:32:45,680 --> 00:32:46,240 LIKELY RADIATION TREATMENT. 722 00:32:46,240 --> 00:32:49,360 THIS IS WHAT WE WANT TO PREVENT 723 00:32:49,360 --> 00:32:51,400 FROM HAPPENING AND I'LL TALK 724 00:32:51,400 --> 00:32:52,880 ABOUT THIS MORE DURING THE TALK. 725 00:32:52,880 --> 00:32:54,360 ONE THING THAT BROUGHT ME IN 726 00:32:54,360 --> 00:32:55,840 TALKING ABOUT THE TREATMENTS 727 00:32:55,840 --> 00:32:58,000 WE'RE DEVELOPING INTO THE PERIOD 728 00:32:58,000 --> 00:33:00,680 AS A PEDIATRIC ONCOLOGIST WAS 729 00:33:00,680 --> 00:33:03,840 THE FACT THE RAS PATHWAY IS 730 00:33:03,840 --> 00:33:06,240 ACTIVATED IN NF 1 AND 731 00:33:06,240 --> 00:33:07,800 PHARMACEUTICAL COMPANIES HAVE 732 00:33:07,800 --> 00:33:11,200 BEEN DEVELOPING DRUGS TO BLOCK 733 00:33:11,200 --> 00:33:13,600 THIS ACTIVATION FOR CANCERS 734 00:33:13,600 --> 00:33:15,040 PREDOMINANTLY FOR MANY YEARS. 735 00:33:15,040 --> 00:33:19,840 WHEN I STARTED IN THE FIELD AND 736 00:33:19,840 --> 00:33:22,800 WE KNOW THAT THROUGH THE 737 00:33:22,800 --> 00:33:28,760 MUTATION OF THE NF IS GENE WE 738 00:33:28,760 --> 00:33:31,040 HAVE SURVIVAL SIGNALS YOU COULD 739 00:33:31,040 --> 00:33:34,680 TARGET, I THOUGHT, EASILY, WITH 740 00:33:34,680 --> 00:33:38,000 MEDICAL INTERVENTIONS SUCH AS 741 00:33:38,000 --> 00:33:45,200 WITH TRANSFERASE INHIBITORS OR 742 00:33:45,200 --> 00:33:47,000 BY SIGNALLING DOWN STREAM OF RAS 743 00:33:47,000 --> 00:33:50,040 YOU SEE ON THE LEFT SIDE. 744 00:33:50,040 --> 00:33:52,760 BUT DISAPPOINTINGLY NONE OF THIS 745 00:33:52,760 --> 00:33:54,440 REALLY WORKED UNTIL WE 746 00:33:54,440 --> 00:33:58,440 IDENTIFIED THE MEK INHIBITERS 747 00:33:58,440 --> 00:33:59,880 AND THE KINASE PATHWAY WERE THE 748 00:33:59,880 --> 00:34:02,000 FIRST TO SHOW ACTIVITY IN THESE 749 00:34:02,000 --> 00:34:06,040 TUMORS AND I TALK ABOUT THIS IN 750 00:34:06,040 --> 00:34:06,880 THE FOLLOWING. 751 00:34:06,880 --> 00:34:12,160 THIS HOLDS TRUE FOR THE BENIGN 752 00:34:12,160 --> 00:34:26,400 HISTOLOGICALLY BENIGN PLEXIFORM 753 00:34:26,400 --> 00:34:26,800 FIB 754 00:34:26,800 --> 00:34:27,200 FIB 755 00:34:27,200 --> 00:34:27,600 FIB 756 00:34:27,600 --> 00:34:30,200 FIBROHISTOMA AND YOU CAN SEE THE 757 00:34:30,200 --> 00:34:33,400 PHOTOGRAPHS IN THE BOTTOM AND 758 00:34:33,400 --> 00:34:35,800 RIGHT AND YOU SEE THEY'RE NOT 759 00:34:35,800 --> 00:34:36,600 BENIGN TUMORS. 760 00:34:36,600 --> 00:34:38,800 AND OUR GOAL SEE IF WE COULD 761 00:34:38,800 --> 00:34:44,080 UNDERSTAND THE GROWTH OF THE 762 00:34:44,080 --> 00:34:51,000 TUMORS AND DEVELOP EFFECTIVE 763 00:34:51,000 --> 00:34:53,880 TREATMENT AND WHAT WE DO IN 764 00:34:53,880 --> 00:34:55,840 CANCER CLINICAL TRIALS WE DO ONE 765 00:34:55,840 --> 00:34:57,200 DIMENSIONAL MEASUREMENTS MEANING 766 00:34:57,200 --> 00:35:02,240 THE LONGEST DIAMETER OR THE 767 00:35:02,240 --> 00:35:05,120 LONGEST PERPENDICULAR DIAMETERS 768 00:35:05,120 --> 00:35:07,840 AND WE SEE PROGRESSION OR 769 00:35:07,840 --> 00:35:10,120 SHRINKAGE QUICKLY BUT FOR NF 1 770 00:35:10,120 --> 00:35:14,520 TUMORS THE PLEXI FORM FIBROMAS 771 00:35:14,520 --> 00:35:31,800 THAT NEEDED A METHOD AND WE HAVE 772 00:35:31,800 --> 00:35:35,240 THIS HERE IN THE ORBITAL TUMOR 773 00:35:35,240 --> 00:35:43,720 AND YOU SEE THE AXIAL PLANE HOW 774 00:35:43,720 --> 00:35:46,320 THIS PUTS A NICE ORDER AROUND 775 00:35:46,320 --> 00:35:50,960 EACH SLICE AND THIS ALLOWS US TO 776 00:35:50,960 --> 00:35:54,120 MEASURE THE TUMORS AND IDENTIFY 777 00:35:54,120 --> 00:35:57,560 SHRINKAGE OR GROWTH MORE 778 00:35:57,560 --> 00:35:58,200 QUICKLY. 779 00:35:58,200 --> 00:36:01,200 SO WE USED THE METHOD IN TWO 780 00:36:01,200 --> 00:36:01,440 WAYS. 781 00:36:01,440 --> 00:36:03,000 ONE IS IN THE NATURAL HISTORY 782 00:36:03,000 --> 00:36:07,000 STUDY AND TWO IS IN CLINICAL 783 00:36:07,000 --> 00:36:08,040 TRIALS AN THIS WORK WAS DONE IN 784 00:36:08,040 --> 00:36:10,240 WHICH YOU CAN SEE ON THE PANEL 785 00:36:10,240 --> 00:36:14,960 ON THE RIGHT IS THE AGE AT THE 786 00:36:14,960 --> 00:36:15,880 INITIAL MRI ON OUR NATURAL 787 00:36:15,880 --> 00:36:18,280 HISTORY STUDY AND EVERY DOT IS A 788 00:36:18,280 --> 00:36:21,200 PATIENT AND ON THE Y AXIS YOU 789 00:36:21,200 --> 00:36:23,680 SEE THE PERCENT GROWTH OR 790 00:36:23,680 --> 00:36:27,200 SHRINKAGE OF THE TUMOR PER YEAR 791 00:36:27,200 --> 00:36:28,840 TO SEE THE YOUNGEST PATIENTS HAD 792 00:36:28,840 --> 00:36:32,560 THE MOST RAPIDLY GROWING TUMORS 793 00:36:32,560 --> 00:36:34,320 WHEREAS LITTLE GROWTH IN OLDER 794 00:36:34,320 --> 00:36:34,640 PATIENTS. 795 00:36:34,640 --> 00:36:35,160 THAT WAS AN IMPORTANT 796 00:36:35,160 --> 00:36:37,600 OBSERVATION FOR US AND WHY WE 797 00:36:37,600 --> 00:36:40,080 TARGETED WITH OUR TREATMENT 798 00:36:40,080 --> 00:36:41,520 TRIALS YOUNG PATIENTS WHO WE 799 00:36:41,520 --> 00:36:43,880 HOPE TO GET THE MOST BENEFIT 800 00:36:43,880 --> 00:36:45,200 FROM THIS. 801 00:36:45,200 --> 00:36:46,800 IN ADDITION, DR. GROSS DOCUMENTS 802 00:36:46,800 --> 00:36:49,200 AT A YOUNG AGE WHEN THE PATIENTS 803 00:36:49,200 --> 00:36:50,800 CAME FROM THE FIRST TIME TO THE 804 00:36:50,800 --> 00:36:53,920 NIH TUMORS WOULD ALREADY HAVE 805 00:36:53,920 --> 00:36:56,800 CAUSED MORBIDITY SUCH AS VISION 806 00:36:56,800 --> 00:37:03,840 LOSS, PAIN, DISFIGUREMENT AND 807 00:37:03,840 --> 00:37:06,200 RARELY REVERSAL. 808 00:37:06,200 --> 00:37:10,000 THIS IS THE FIRST BIG CLINICAL 809 00:37:10,000 --> 00:37:15,040 TRIAL I CONDUCTED AND THIS WAS A 810 00:37:15,040 --> 00:37:18,600 DOUBLE-BLINDED 811 00:37:18,600 --> 00:37:23,800 PLACEBO-CONTROLLED WITH KIDS 812 00:37:23,800 --> 00:37:25,800 WITH GROWING NEUROFIBROMATOSIS 813 00:37:25,800 --> 00:37:29,000 WITH A FLIP OF A COIN DECIDED IF 814 00:37:29,000 --> 00:37:30,960 THEY GOT SELUMETINIB OR A 815 00:37:30,960 --> 00:37:31,200 PLACEBO. 816 00:37:31,200 --> 00:37:33,640 WE DIDN'T KNOW WHAT THE KIDS 817 00:37:33,640 --> 00:37:34,280 WERE RECEIVING. 818 00:37:34,280 --> 00:37:35,560 THE KIDS DIDN'T KNOW AND THE 819 00:37:35,560 --> 00:37:38,000 PARENTS DIDN'T KNOW WHAT THEY 820 00:37:38,000 --> 00:37:39,040 WERE RECEIVING. 821 00:37:39,040 --> 00:37:42,600 WE WOULD FOLLOW THE PATIENTS 822 00:37:42,600 --> 00:37:48,800 WITH THE MRI UNTIL THE TUMOR WAS 823 00:37:48,800 --> 00:37:54,000 SHOWN TO BE GROWING AND CHANGED 824 00:37:54,000 --> 00:37:58,200 THEIR RECEIVING STATUS AND THIS 825 00:37:58,200 --> 00:38:00,200 DID NOT RESULT IN THE DESIRED 826 00:38:00,200 --> 00:38:01,960 GROWING OF THE GROWTH. 827 00:38:01,960 --> 00:38:12,360 WE HAVE A SURVIVAL PERCENTAGE 828 00:38:12,360 --> 00:38:20,520 AND IDEALLY WE'D LIKE TO SEE 829 00:38:20,520 --> 00:38:23,040 100% SURVIVAL AND YOU CAN SEE 830 00:38:23,040 --> 00:38:24,360 MOST THE PATIENTS DEVELOPED 831 00:38:24,360 --> 00:38:27,800 TUMOR GROWTH AND THERE WAS 832 00:38:27,800 --> 00:38:30,800 REALLY NO DIFFERENCE BETWEEN 833 00:38:30,800 --> 00:38:34,480 PLACEBO AND THIS PHARMACEUTICAL 834 00:38:34,480 --> 00:38:35,800 AND WE CONDUCTED CLINICAL TRIALS 835 00:38:35,800 --> 00:38:39,520 WITH THE GOAL IMPROVE ON THIS 836 00:38:39,520 --> 00:38:42,440 AND YOU SEE THE CURVE FOR THE 837 00:38:42,440 --> 00:38:45,920 OTHER CLINICAL TRIAL AND THE 838 00:38:45,920 --> 00:38:54,080 BEST DRUG WAS AN IMMUNE 839 00:38:54,080 --> 00:38:55,800 MODULATORY AGENT WHERE WE 840 00:38:55,800 --> 00:38:58,360 INCREASED THE TIME TO PROGRESS 841 00:38:58,360 --> 00:39:01,000 OF 29 MONTHS COMPARED TO THE 842 00:39:01,000 --> 00:39:02,000 PLACEBO. 843 00:39:02,000 --> 00:39:05,320 HOWEVER WE HAD TUMOR SHRINKAGE 844 00:39:05,320 --> 00:39:09,200 IN ONLY FEW PATIENTS AND WHEN 845 00:39:09,200 --> 00:39:11,280 YOU HAVE A CHRONIC CONDITION 846 00:39:11,280 --> 00:39:13,080 LIKE NF 1 IT WASN'T ENCOURAGING 847 00:39:13,080 --> 00:39:14,800 AND I WASN'T READY TO GIVE UP 848 00:39:14,800 --> 00:39:17,920 BUT IT WAS SOBERING WE HAD 849 00:39:17,920 --> 00:39:20,480 PATIENTS THAT HAD GONE ON 850 00:39:20,480 --> 00:39:22,320 CLINICAL TRIALS NOT SEEING CLEAR 851 00:39:22,320 --> 00:39:24,000 TUMOR SHRINKAGE BUT PROGRESSION 852 00:39:24,000 --> 00:39:27,200 OF THE TUMOR AS WE SEE IN THE 3 853 00:39:27,200 --> 00:39:30,480 AND 4-YEAR-OLD. 854 00:39:30,480 --> 00:39:33,960 NOT ONLY MORE VISIBLE DIG 855 00:39:33,960 --> 00:39:36,200 FIGURATIVE BUT THE BOY UNDERWENT 856 00:39:36,200 --> 00:39:39,680 ADDITIONAL SURGERIES AND PAIN 857 00:39:39,680 --> 00:39:43,040 MEDICATIONS AND DEVELOPED BOWEL 858 00:39:43,040 --> 00:39:44,400 INCONTINENCE SO WE FELT WE 859 00:39:44,400 --> 00:39:45,600 NEEDED TO MAKE PROGRESS FOR THE 860 00:39:45,600 --> 00:39:47,360 PATIENTS. 861 00:39:47,360 --> 00:39:48,800 THEN WE CONDUCTED A CLINICAL 862 00:39:48,800 --> 00:39:53,120 TRIAL WITH A MEK INHIBITOR 863 00:39:53,120 --> 00:39:58,000 BLOCKING THE MEK KINASE. 864 00:39:58,000 --> 00:39:59,800 THIS TRIAL SHOWED SUBSTANTIAL 865 00:39:59,800 --> 00:40:02,640 PROMISE IN THAT EVERY PATIENT 866 00:40:02,640 --> 00:40:08,320 HAD AT LEAST SOME TUMOR 867 00:40:08,320 --> 00:40:11,360 SHRINKAGE AND THE TUMOR VOLUME 868 00:40:11,360 --> 00:40:13,200 SHOWN IN EVERYTHING NEGATIVE 869 00:40:13,200 --> 00:40:15,400 MEANING THE BLACK BAR HAS A 870 00:40:15,400 --> 00:40:17,880 DOWNWARD TREND MEANS TUMOR 871 00:40:17,880 --> 00:40:18,200 SHRINKAGE. 872 00:40:18,200 --> 00:40:22,680 WE HAD NEVER SEEN THIS BEFORE 873 00:40:22,680 --> 00:40:24,920 AND WE ALSO SAW SOME CLINIC 874 00:40:24,920 --> 00:40:33,080 IMPROVEMENT WITH IMPROVEMENT IN 875 00:40:33,080 --> 00:40:34,000 DISFIGUREMENT WE TALKED BIG THE 876 00:40:34,000 --> 00:40:35,800 FDA BECAUSE WE'RE EXCITED ABOUT 877 00:40:35,800 --> 00:40:37,960 THE FINDING AND ASK IF THEY 878 00:40:37,960 --> 00:40:40,280 WOULD GIVE YOU WILLS WHAT THEY 879 00:40:40,280 --> 00:40:41,720 CALL BREAKTHROUGH THERAPY 880 00:40:41,720 --> 00:40:43,160 DESIGNATION BUT THEY SAID YOU'RE 881 00:40:43,160 --> 00:40:44,760 SHRINKING THE TUMORS BUT YOU 882 00:40:44,760 --> 00:40:47,840 NEED TO SHOW US PATIENTS HAVE 883 00:40:47,840 --> 00:40:55,000 TRUE CLINICAL BENEFIT FROM THIS. 884 00:40:55,000 --> 00:40:57,520 YOU NEED TO GO BACK TO THE 885 00:40:57,520 --> 00:40:58,720 DRAWING BOARD AND SO WE DESIGNED 886 00:40:58,720 --> 00:41:01,120 A LARGER STUDY FOR PATIENTS WHO 887 00:41:01,120 --> 00:41:02,800 HAD SOME SYMPTOMS WHEN THEY 888 00:41:02,800 --> 00:41:05,520 ENROLLED ON THIS STUDY. 889 00:41:05,520 --> 00:41:07,560 WE USED THE TUMOR MEASUREMENTS 890 00:41:07,560 --> 00:41:10,240 AS THE PRIMARY END POINT. 891 00:41:10,240 --> 00:41:13,280 YOU CAN SEE OB THIS WATER FALL 892 00:41:13,280 --> 00:41:14,840 PLOT WHEN YOU LOOK AT ZERO 893 00:41:14,840 --> 00:41:17,040 ALMOST ALL THE BARS WENT DOWN 894 00:41:17,040 --> 00:41:18,360 AND THE RID DOTTED LINE SHOWS 895 00:41:18,360 --> 00:41:22,600 THROUGH THE NUMBER OF PATIENTS 896 00:41:22,600 --> 00:41:25,320 WHO HAD MORE THAN 20% TUMOR 897 00:41:25,320 --> 00:41:29,440 SHRINKAGE BY VOLUME. 898 00:41:29,440 --> 00:41:34,720 WE WERE ABLE TO SHOW WITH 899 00:41:34,720 --> 00:41:38,000 METICULOUS DOCUMENTATION WE SAW 900 00:41:38,000 --> 00:41:43,520 SIGNIFICANT DISFIGUREMENT TO 901 00:41:43,520 --> 00:41:45,600 CYCLE 37 THERE'S CONTINUOUS 902 00:41:45,600 --> 00:41:47,600 IMPROVEMENT AND WE LOOKED AT 903 00:41:47,600 --> 00:41:50,000 PATIENT-REPORTED AND 904 00:41:50,000 --> 00:41:57,920 PARENT-REPORTED OUTCOMES THEY 905 00:41:57,920 --> 00:42:00,760 SELF-REPORTED AND THERE WAS AN 906 00:42:00,760 --> 00:42:02,040 OVERALL IMPROVEMENT IN 907 00:42:02,040 --> 00:42:06,160 MORBIDITIES RELATED TO THEIR 908 00:42:06,160 --> 00:42:07,440 PLEXIFORM NEUROFIBROMA AND THEN 909 00:42:07,440 --> 00:42:09,200 LOOKED AT PATIENT-REPORTED 910 00:42:09,200 --> 00:42:10,560 OUTCOME MEASURES OF PAIN 911 00:42:10,560 --> 00:42:11,240 INTENSITY. 912 00:42:11,240 --> 00:42:13,000 THIS WAS WORK DONE BY 913 00:42:13,000 --> 00:42:16,200 DR. WALTERS AND DR. MARTIN WHO 914 00:42:16,200 --> 00:42:18,320 SHOWED THAT COMPARING BASELINE 915 00:42:18,320 --> 00:42:29,560 TO PREPSY CYCLE THERE WAS A 916 00:42:29,560 --> 00:42:30,280 REDUCTION CLINICALLY MEANINGFUL 917 00:42:30,280 --> 00:42:33,800 AND IN TUMOR INTENSITY AND IN 918 00:42:33,800 --> 00:42:34,120 INTERFERENCE. 919 00:42:34,120 --> 00:42:37,280 THESE FINDINGS WERE VERY 920 00:42:37,280 --> 00:42:38,760 IMPORTANT FOR THE SUBSEQUENT FDA 921 00:42:38,760 --> 00:42:41,400 APPROVAL BECAUSE THEY WERE ABLE 922 00:42:41,400 --> 00:42:46,280 TO DOCUMENT NOT ONLY THE TUMOR 923 00:42:46,280 --> 00:42:47,840 SHRANK BUT IT WAS CLINICALLY 924 00:42:47,840 --> 00:42:48,320 MEANINGFUL. 925 00:42:48,320 --> 00:42:50,400 I WANT TO SHOW ONE MORE EXAMPLE 926 00:42:50,400 --> 00:42:52,800 OF AN 8-YEAR-OLD GIRL WITH A 927 00:42:52,800 --> 00:42:55,840 TUMOR THAT OBSTRUCT THE AIRWAY 928 00:42:55,840 --> 00:42:59,400 AND HAD A TRACHEOSTOMY TO HELP 929 00:42:59,400 --> 00:42:59,840 HER BREATHE. 930 00:42:59,840 --> 00:43:04,920 YOU SEE AN MRI AND THE BLUE 931 00:43:04,920 --> 00:43:08,000 ARROWS POINT TO THE AIRWAY WHILE 932 00:43:08,000 --> 00:43:10,560 THE TUMOR ONLY SHRANK BY 25% OR 933 00:43:10,560 --> 00:43:14,000 SO THE AIRWAY DID OPEN UP, THE 934 00:43:14,000 --> 00:43:17,560 PATIENT COULD BE DECANNULATED 935 00:43:17,560 --> 00:43:19,840 AND CONTINUES ON TREATMENT TO 936 00:43:19,840 --> 00:43:23,880 DATE WITHOUT THE NEED FOR AN 937 00:43:23,880 --> 00:43:26,600 ARTIFICIAL HELP. 938 00:43:26,600 --> 00:43:28,240 THAT WAS A MAJOR ADVANCEMENT FOR 939 00:43:28,240 --> 00:43:29,000 THE SPECIFIC PATIENT. 940 00:43:29,000 --> 00:43:31,800 I WANT TO DRIVE ONE OTHER POINT 941 00:43:31,800 --> 00:43:33,600 HERE. 942 00:43:33,600 --> 00:43:39,880 THIS IS ONE OF THE BOYS, WYATT, 943 00:43:39,880 --> 00:43:42,800 STARTING AT 5 YEARS OLD AND HIS 944 00:43:42,800 --> 00:43:45,000 TUMOR GREW RELENTLESS. 945 00:43:45,000 --> 00:43:47,120 WE THEN STARTED THE MEK 946 00:43:47,120 --> 00:43:51,240 INHIBITOR AND HAD TUMOR 947 00:43:51,240 --> 00:43:53,400 SHRINKAGE AND HAD TO STOP 948 00:43:53,400 --> 00:43:57,760 TEMPORARILY BECAUSE OF THE LEFT 949 00:43:57,760 --> 00:43:58,480 VENTRICULAR CARDIAC FUNCTION 950 00:43:58,480 --> 00:44:03,720 THIS IS OBVIOUSLY IMPORTANT. 951 00:44:03,720 --> 00:44:06,360 WE STOPPED THE TREATMENT THE 952 00:44:06,360 --> 00:44:10,800 TUMOR STARTED AND STARTED AT A 953 00:44:10,800 --> 00:44:11,520 REDUCED DOSE AND THEY CONTINUE 954 00:44:11,520 --> 00:44:16,920 ON TREATMENT TO DATE BUT IT 955 00:44:16,920 --> 00:44:19,840 SHOWS IT'S NOT A CURE IT HAPPENS 956 00:44:19,840 --> 00:44:24,120 AND PATIENTS NEED TO BE ON IT 957 00:44:24,120 --> 00:44:25,240 LIKE ON BLOOD PRESSURE MEDICINE 958 00:44:25,240 --> 00:44:27,840 TO MAKE SURE WE HAVE A 959 00:44:27,840 --> 00:44:35,040 CONTINUOUS POSITIVE EFFECT. 960 00:44:35,040 --> 00:44:41,680 FOR THE MOST PART IT'S WELL 961 00:44:41,680 --> 00:44:50,040 TOLERATED AND THE MOST FREQUENT 962 00:44:50,040 --> 00:44:54,760 ARE NAUSEA AND VOMITING AND 963 00:44:54,760 --> 00:44:56,400 SOMETHING WHICH IS AN 964 00:44:56,400 --> 00:44:58,800 INFLAMMATION AROUND THE NAIL BED 965 00:44:58,800 --> 00:44:59,840 WHICH CAN LOOK QUITE AGGRESSIVE 966 00:44:59,840 --> 00:45:03,000 AS YOU CAN SEE BUT WE DEVELOPED 967 00:45:03,000 --> 00:45:08,000 GOOD TREATMENT APPROACHES. 968 00:45:08,000 --> 00:45:27,520 SO MOST PATIENTS CAN THIS SHOWS 969 00:45:27,520 --> 00:45:29,400 CHILDREN TREATED ON THE TRIAL 970 00:45:29,400 --> 00:45:31,520 AND MOST PATIENTS HAD A VOLUME 971 00:45:31,520 --> 00:45:33,760 REDUCTION AND THEN YOU SEE AN 972 00:45:33,760 --> 00:45:34,480 AGE-MATCHED CONTROL COMPARISON 973 00:45:34,480 --> 00:45:39,200 FOR PATIENTS ON THE NATURAL 974 00:45:39,200 --> 00:45:40,880 HISTORY STUDY WHO DID NOT 975 00:45:40,880 --> 00:45:44,560 RECEIVE THE MEC INHIBITOR AND 976 00:45:44,560 --> 00:45:47,880 HAD GROWTH IN TUMORS AND I'M 977 00:45:47,880 --> 00:45:53,800 COMING BACK TO THE KAPLAN MEIER 978 00:45:53,800 --> 00:45:55,880 CURVE AND KIDS ON THE NATURAL 979 00:45:55,880 --> 00:45:58,680 HISTORY STUDY HAD PROGRESSIVE 980 00:45:58,680 --> 00:46:02,040 TUMORS WITH A MEDIAN 981 00:46:02,040 --> 00:46:03,680 REGRESSION-FREE SURVIVAL OF 1.3 982 00:46:03,680 --> 00:46:07,840 YEARS COMPARED TO KIDS WHO 983 00:46:07,840 --> 00:46:11,800 RECEIVE SELUMETINIB WHERE 84% 984 00:46:11,800 --> 00:46:13,840 WERE PROGRESSION FREE IN YEARS. 985 00:46:13,840 --> 00:46:18,720 THIS IS IMPORTANT TOWARDS THE 986 00:46:18,720 --> 00:46:29,320 NAD APREEFL -- AND HERE YOU SEE 987 00:46:29,320 --> 00:46:31,000 IT COMPARED TO OTHER CLINICAL 988 00:46:31,000 --> 00:46:31,280 TRIALS. 989 00:46:31,280 --> 00:46:36,360 ALL THIS DATA WAS SUBMITTED TO 990 00:46:36,360 --> 00:46:42,000 THE FDA AND DR. AREA ASKED THE 991 00:46:42,000 --> 00:46:43,840 NF 1 GENE WAS DISCOVERED BY 992 00:46:43,840 --> 00:46:49,400 DR. COLLINS AND DR. RAY WHITE. 993 00:46:49,400 --> 00:46:53,840 IT TOOK 30 YEARS TO FOR APPROVAL 994 00:46:53,840 --> 00:46:58,600 FOR KIDS WITH SYMPTOMATIC AND 995 00:46:58,600 --> 00:46:59,880 PLEXIFORM NEUROFIBROMAS. 996 00:46:59,880 --> 00:47:03,600 BASED ON THE TRIAL THERE'S 997 00:47:03,600 --> 00:47:06,920 APPROVAL IN MORE THAN 13 998 00:47:06,920 --> 00:47:08,440 COUNTRIES AND MORE COMING. 999 00:47:08,440 --> 00:47:11,840 THIS MARATHON HAS PAID OFF BUT I 1000 00:47:11,840 --> 00:47:18,040 THINK THERE'S MORE TO DO. 1001 00:47:18,040 --> 00:47:19,680 THERE'S A TRIAL BROSE WILL BE 1002 00:47:19,680 --> 00:47:25,480 LEADING LOOKING AT NOT ONLY CAN 1003 00:47:25,480 --> 00:47:28,320 WE REDUCE MORBIDITY AND 1004 00:47:28,320 --> 00:47:31,920 TREATMENTS TUMORS BUT PREVENT 1005 00:47:31,920 --> 00:47:34,800 THEM FROM BECOMING SYSTEMATIC 1006 00:47:34,800 --> 00:47:37,800 AND YOU CAN SEE OVER TIME THIS 1007 00:47:37,800 --> 00:47:40,440 LITTLE GIRL DEVELOPED A 1008 00:47:40,440 --> 00:47:41,760 DISFIGURING FACIAL TUMOR AND 1009 00:47:41,760 --> 00:47:43,600 WHAT DR. BROSE WANTS DO IS START 1010 00:47:43,600 --> 00:47:47,560 THE INHIBITOR IN THE CHILD WHEN 1011 00:47:47,560 --> 00:47:51,400 IT'S AN ASYMPTOMATIC PLEXIFORM 1012 00:47:51,400 --> 00:47:53,000 NEUROFIBROMA AND WANT TO SHOW WE 1013 00:47:53,000 --> 00:47:59,800 CAN PREVENT THESE FROM 1014 00:47:59,800 --> 00:48:00,960 HAPPENING. 1015 00:48:00,960 --> 00:48:03,800 A TRIAL IS AMBITIOUS AND WE LOOK 1016 00:48:03,800 --> 00:48:07,600 AT THE INCIDENTS AND USE WHOLE 1017 00:48:07,600 --> 00:48:08,480 BODY MRI. 1018 00:48:08,480 --> 00:48:13,560 IN THE SECOND PART WE'LL HAVE A 1019 00:48:13,560 --> 00:48:15,800 RANDOMIZED COMPARISON OF 1020 00:48:15,800 --> 00:48:17,800 ASYMPTOMATIC TUMORS TREAT AND 1021 00:48:17,800 --> 00:48:20,920 OBSERVED AND IN THE THIRD PART 1022 00:48:20,920 --> 00:48:22,600 THEY'LL LOOK AT THE DIFFERENT 1023 00:48:22,600 --> 00:48:23,800 SCHEDULE LOOKING AT A DIFFERENT 1024 00:48:23,800 --> 00:48:25,080 SCHEDULE AND LOWER DOSE TO SEE 1025 00:48:25,080 --> 00:48:37,120 IF WE CAN SUSTAIN THE BENEFIT. 1026 00:48:37,120 --> 00:48:39,280 I'LL KNOW TALK IN LESS DURATION 1027 00:48:39,280 --> 00:48:42,640 BECAUSE WE HAVE LESS DATA ABOUT 1028 00:48:42,640 --> 00:48:43,680 THE MALIGNANT TUMORS THAT 1029 00:48:43,680 --> 00:48:47,840 DEVELOP IN UP TO 16% OF PEOPLE 1030 00:48:47,840 --> 00:48:50,520 WITH NF 1 AND OUR EFFORTS TO 1031 00:48:50,520 --> 00:48:53,520 PREVENT THE DEVELOPMENT OF MPNST 1032 00:48:53,520 --> 00:48:59,200 BY FOCUSSING ON THE ATYPICAL 1033 00:48:59,200 --> 00:49:00,880 NEUROFIBROMAS. 1034 00:49:00,880 --> 00:49:01,680 THE TUMORS ARE AGGRESSIVE 1035 00:49:01,680 --> 00:49:03,800 SUBTISSUE SARCOMAS. 1036 00:49:03,800 --> 00:49:05,720 AND COMPLETE SURGICAL RESECTION 1037 00:49:05,720 --> 00:49:07,240 WITH NEGATIVE MARGINS MEANING 1038 00:49:07,240 --> 00:49:09,920 THERE'S NO TUMOR CELL LEFT IS 1039 00:49:09,920 --> 00:49:10,560 REQUIRED. 1040 00:49:10,560 --> 00:49:17,800 IN PATIENTS WHERE THIS CANNOT BE 1041 00:49:17,800 --> 00:49:19,800 ACHURD WE HAVE DONE A NUMBER OF 1042 00:49:19,800 --> 00:49:20,400 CLINICAL TRIALS AND MOST ARE 1043 00:49:20,400 --> 00:49:26,000 PHASE 2 TRIALS AND WANTED TO 1044 00:49:26,000 --> 00:49:29,200 KNOW IF WE REDUCED TUMORS OR 1045 00:49:29,200 --> 00:49:31,160 SLOWED PROGRESSION. 1046 00:49:31,160 --> 00:49:33,080 UNFORTUNATELY WE'VE NOT BEEN 1047 00:49:33,080 --> 00:49:33,400 SUCCESSFUL. 1048 00:49:33,400 --> 00:49:35,760 THE TILES WERE FEASIBLE BUT WE 1049 00:49:35,760 --> 00:49:37,960 HAVE NOT SEEN MAJOR SHRINKAGE OR 1050 00:49:37,960 --> 00:49:42,760 DELAYING IN THE TIME TO 1051 00:49:42,760 --> 00:49:43,280 PROGRESSION. 1052 00:49:43,280 --> 00:49:47,200 WITH THAT IN MIND WE FOCUSSED AT 1053 00:49:47,200 --> 00:49:51,400 LOOKING AT PRE MALIGNANT TUMORS 1054 00:49:51,400 --> 00:49:52,760 USING WHOLE BODY MRI. 1055 00:49:52,760 --> 00:49:55,840 ON THE LEFT YOU SEE THE CRONAL 1056 00:49:55,840 --> 00:50:00,600 MRI AND LARGE TUMOR WITH A PRE 1057 00:50:00,600 --> 00:50:01,680 MALIGNANT LESION. 1058 00:50:01,680 --> 00:50:09,120 ON THE RIGHT YOU SEE ANOTHER MRI 1059 00:50:09,120 --> 00:50:11,400 WHERE I HOPE YOU CAN DETECT THE 1060 00:50:11,400 --> 00:50:14,000 NODULES AND THOSE WE BELIEVE ARE 1061 00:50:14,000 --> 00:50:15,800 PRE MALIGNANT. 1062 00:50:15,800 --> 00:50:21,560 WE IDENTIFIED IN PATIENTS WITHIN 1063 00:50:21,560 --> 00:50:24,680 PLEXIFORM NEUROFIBROMAZ AN AS 1064 00:50:24,680 --> 00:50:27,960 THE ARROWS INDICATE MANY LESIONS 1065 00:50:27,960 --> 00:50:33,600 APPEAR AS DISTINCT NODULES. 1066 00:50:33,600 --> 00:50:39,720 THEY'RE BRIGHT IN COMPARE TO NO 1067 00:50:39,720 --> 00:50:42,800 SIGNAL IN PLEXIFORM PLEXIFORM 1068 00:50:42,800 --> 00:50:44,000 AND DEVELOP LATER IN LIFE NOT IN 1069 00:50:44,000 --> 00:50:45,800 YOUNG PATIENTS. 1070 00:50:45,800 --> 00:50:47,840 YOU CAN SEE THIS NICELY IN THE 1071 00:50:47,840 --> 00:50:51,840 UPPER PANEL WHERE YOU SEE A 90 1072 00:50:51,840 --> 00:50:54,560 YEARS WITH A PLEXIFORM FIBROMA 1073 00:50:54,560 --> 00:50:55,200 OF THE NECK. 1074 00:50:55,200 --> 00:50:58,320 WHEN SHE'S 15 AND LOOK AT THE 1075 00:50:58,320 --> 00:51:02,920 RED ARROW, THERE'S A DISTINCT 1076 00:51:02,920 --> 00:51:06,760 NODULE NOT THERE AT 9 YEARS OF 1077 00:51:06,760 --> 00:51:13,520 AGE AND GREW RAPIDLY. 1078 00:51:13,520 --> 00:51:15,480 WHEN IT WAS IN THE PROCESS OF 1079 00:51:15,480 --> 00:51:21,120 TRANSFORMING TO BECOME 1080 00:51:21,120 --> 00:51:21,520 MALIGNANT. 1081 00:51:21,520 --> 00:51:25,240 YOU SEE AND THE LOWER PANEL 1082 00:51:25,240 --> 00:51:27,760 COMPARED TO PLEXIFORM 1083 00:51:27,760 --> 00:51:29,000 NEUROFIBROMAS THEY DON'T SLOW 1084 00:51:29,000 --> 00:51:30,720 DOWN AND IN PATIENT THE GROWTH 1085 00:51:30,720 --> 00:51:39,800 RATE IS IN DEPENDENT OF AGE. 1086 00:51:39,800 --> 00:51:46,320 AND CERTAIN PATHOLOGIC FEATURES 1087 00:51:46,320 --> 00:51:49,640 ARE CALLED NEUROPLASMS OF 1088 00:51:49,640 --> 00:51:51,200 POTENTIAL AND MANY HAVE A CHANGE 1089 00:51:51,200 --> 00:51:54,280 DR. SHERN WILL TALK ABOUT 1090 00:51:54,280 --> 00:51:57,840 MOMENTARILY CALLED CDK AND OUR 1091 00:51:57,840 --> 00:52:03,840 FOCUS IS ON SURGICAL RESECTION 1092 00:52:03,840 --> 00:52:11,800 OF THE TUMORS PRIOR TO BECOMING 1093 00:52:11,800 --> 00:52:14,560 MALIGNANT. 1094 00:52:14,560 --> 00:52:21,000 THERE WAS AN UPPER ARM 1095 00:52:21,000 --> 00:52:23,760 NEUROFIBROMA AND VOLUMETRIC 1096 00:52:23,760 --> 00:52:25,520 ANALYSIS SHOWED IT WAS GROWING 1097 00:52:25,520 --> 00:52:27,040 SLOWLY OVER TIME WITH THE 1098 00:52:27,040 --> 00:52:30,480 HYPOTHESIS IT WAS A PRECURSOR 1099 00:52:30,480 --> 00:52:36,760 LESION FOR MPNST. 1100 00:52:36,760 --> 00:52:38,520 WE COULD NOT PREDICT BUT IT DID 1101 00:52:38,520 --> 00:52:39,840 TRANSFORM AND YOU CAN SEE IN THE 1102 00:52:39,840 --> 00:52:46,200 RED LINE IT GREW MORE QUICKLY 1103 00:52:46,200 --> 00:52:47,360 ALL OF A SUDDEN AND WE'RE 1104 00:52:47,360 --> 00:52:48,800 STRUGGLING THE RIGHT TIME TO 1105 00:52:48,800 --> 00:52:55,840 INTERVENE AND HOW CAN WE PREDICT 1106 00:52:55,840 --> 00:52:59,600 MALIGNANT TRANSFORMATION. 1107 00:52:59,600 --> 00:53:03,280 WE'RE WORKING ON A NEW STUDY 1108 00:53:03,280 --> 00:53:07,000 FOCUSSING ON CHARACTERIZING THE 1109 00:53:07,000 --> 00:53:10,000 MALIGNANT INTERVENTION INCLUDING 1110 00:53:10,000 --> 00:53:11,720 SURGICAL RESECTION WITH OUR 1111 00:53:11,720 --> 00:53:18,480 NEUROSURGEON AND THE STUDY IS IN 1112 00:53:18,480 --> 00:53:23,000 DEVELOPMENT AND HOPEFULLY MAKE 1113 00:53:23,000 --> 00:53:23,280 PROGRESS. 1114 00:53:23,280 --> 00:53:24,480 I'M PLEASED DR. SHERN WILL TALK 1115 00:53:24,480 --> 00:53:26,000 ABOUT THE AMAZING WORK HIS TEAM 1116 00:53:26,000 --> 00:53:27,800 IS DOING TO UNDERSTAND THE 1117 00:53:27,800 --> 00:53:33,000 BIOLOGY AND HOPEFULLY MAKE MORE 1118 00:53:33,000 --> 00:53:38,600 STRIDES IN THE PREVENTION OF 1119 00:53:38,600 --> 00:53:39,720 MPNST. 1120 00:53:39,720 --> 00:53:40,360 I'LL STOP SHARING TO HE CAN TAKE 1121 00:53:40,360 --> 00:53:40,680 OVER. 1122 00:53:40,680 --> 00:53:43,880 >> THANK YOU, DR. WIDEMANN OR 1123 00:53:43,880 --> 00:53:47,520 SETTING ME UP TO TELL THE CROWD 1124 00:53:47,520 --> 00:53:48,680 ABOUT WHAT WE'RE WORK IN THE 1125 00:53:48,680 --> 00:53:49,880 LABORATORY TO FOLLOW-UP ON SOME 1126 00:53:49,880 --> 00:53:54,040 OF THESE STUDIES THAT HAVE BEEN 1127 00:53:54,040 --> 00:53:56,120 SO SUCCESSFUL IN THE CLINICAL. 1128 00:53:56,120 --> 00:53:59,760 I'M A CLINICIAN SCIENTIST AND 1129 00:53:59,760 --> 00:54:09,680 WORK IN THE PEDIATRIC ONCOLOGY 1130 00:54:09,680 --> 00:54:12,080 BRANCH AT THE NCI. 1131 00:54:12,080 --> 00:54:13,080 I SPENT A LOT OF TIME SEQUENCING 1132 00:54:13,080 --> 00:54:15,640 TUMORS AND LOOKING FOR THE 1133 00:54:15,640 --> 00:54:17,440 CHANGES IN TUMORS OVER TIME AND 1134 00:54:17,440 --> 00:54:22,480 WHEN I STARTED MY LAB I WAS 1135 00:54:22,480 --> 00:54:23,640 STRUCK BY THIS DISEASE BECAUSE I 1136 00:54:23,640 --> 00:54:27,280 THINK IT'S A TREMENDOUS TEACHER 1137 00:54:27,280 --> 00:54:28,920 OF TWO POINTS. 1138 00:54:28,920 --> 00:54:34,920 THEY'RE RELATED BUT I THINK 1139 00:54:34,920 --> 00:54:36,600 THEY'RE IMPORTANT AND HOW WE 1140 00:54:36,600 --> 00:54:38,680 STUDY PATIENTS AND HOW THEY 1141 00:54:38,680 --> 00:54:39,320 EVOLVE OVER TIME. 1142 00:54:39,320 --> 00:54:44,960 FIRST IS THERE'S A GENETIC TUMOR 1143 00:54:44,960 --> 00:54:45,280 PROGRESSION. 1144 00:54:45,280 --> 00:54:48,920 DR. WIDEMANN LAID OUT THE 1145 00:54:48,920 --> 00:54:53,880 CLINICAL PROGRESSION. 1146 00:54:53,880 --> 00:54:56,280 IT HAS TO BE ENCODED IN THE 1147 00:54:56,280 --> 00:54:58,320 CANCER CELLS THAT ALLOW IT TO 1148 00:54:58,320 --> 00:55:01,880 PROGRESS OVER TIME. 1149 00:55:01,880 --> 00:55:04,920 THE SECOND POINT IS THESE ARE 1150 00:55:04,920 --> 00:55:08,400 MASSIVE TUMORS. 1151 00:55:08,400 --> 00:55:10,600 THESE BENIGN PLEXIFORM FIBROMAS 1152 00:55:10,600 --> 00:55:12,880 ARE MASSIVE IN SOME PATIENTS AND 1153 00:55:12,880 --> 00:55:14,800 YOU CAN IMAGINE THERE'S A LARGE 1154 00:55:14,800 --> 00:55:21,720 DEGREE OF TUMOR CELLULAR GENEITY 1155 00:55:21,720 --> 00:55:24,200 AND THERE'S A DIVERSITY OF 1156 00:55:24,200 --> 00:55:25,920 CANCER AND IMMUNE AND STROMAL 1157 00:55:25,920 --> 00:55:32,680 CELLS THAT MAKE UP THE TUMOR 1158 00:55:32,680 --> 00:55:33,080 MICROENVIRONMENT. 1159 00:55:33,080 --> 00:55:35,280 THIS IS CRITICAL GOING FORWARD 1160 00:55:35,280 --> 00:55:40,120 AND I'M A CANCER GENETICISTS. 1161 00:55:40,120 --> 00:55:43,680 THIS IS AN ELEGANT DEMONSTRATION 1162 00:55:43,680 --> 00:55:57,280 OF HOW TUMORS EVOLVE OVER TIME. 1163 00:55:57,280 --> 00:55:59,040 THEY HAVE A GERM LINE MUTATION. 1164 00:55:59,040 --> 00:56:02,760 THEY'RE SET UP LIKE THIS WITH 1165 00:56:02,760 --> 00:56:04,680 RAS PATHWAY ACTIVATION YOU'VE 1166 00:56:04,680 --> 00:56:07,960 HEARD THESE WERE FIRST DESCRIBED 1167 00:56:07,960 --> 00:56:12,680 IN 1990 AND FRANCIS COLLINS WAS 1168 00:56:12,680 --> 00:56:13,720 ONE THEIR INVESTIGATORS 1169 00:56:13,720 --> 00:56:16,880 INITIALLY INVOLVED IN THE 1170 00:56:16,880 --> 00:56:23,320 DISCOVERY OF THESE GENES. 1171 00:56:23,320 --> 00:56:26,880 THE PLEXIFORM NEUROFIBROMAS TOOK 1172 00:56:26,880 --> 00:56:30,560 MORE TIME BEFORE WE SAW IT WAS A 1173 00:56:30,560 --> 00:56:34,040 UNIQUE LOSS OF THE ALLELE THAT 1174 00:56:34,040 --> 00:56:39,080 CAUSED THE SPECIFIC CHANGE IN 1175 00:56:39,080 --> 00:56:42,240 THE PATIENTS. 1176 00:56:42,240 --> 00:56:48,040 AND WITH WE HAD AN EXPLOSION OF 1177 00:56:48,040 --> 00:56:50,080 INFORMATION AND SEEING TP53 1178 00:56:50,080 --> 00:56:52,880 MUTATIONS AN ALTERATIONS IN TWO 1179 00:56:52,880 --> 00:56:57,680 GENES EED AND SUS 12 INVOLVED IN 1180 00:56:57,680 --> 00:57:04,320 THE POLY COMER COMPLEXES AND 1181 00:57:04,320 --> 00:57:06,200 EPIGENETIC COMPLEXES IN THE 1182 00:57:06,200 --> 00:57:12,960 CELLS AND IT CAN BE QUITE 1183 00:57:12,960 --> 00:57:16,600 GENETICALLY DIFFERENT THAN THE 1184 00:57:16,600 --> 00:57:21,480 PLEXIFORM ALTERATIONS AND WE 1185 00:57:21,480 --> 00:57:23,840 THINK THERE'S AN INTERMEDIATE 1186 00:57:23,840 --> 00:57:24,880 COUPLE STEPS AND WHAT'S BEEN 1187 00:57:24,880 --> 00:57:28,760 DISCOVERED IS THE LOSS OF THE 1188 00:57:28,760 --> 00:57:32,600 TUMOR SUPPRESSER CDKN2A AND 1189 00:57:32,600 --> 00:57:37,640 USUALLY IT'S ONE ALLELE BUT 1190 00:57:37,640 --> 00:57:38,280 SOMETIMES TWO. 1191 00:57:38,280 --> 00:57:40,720 UNDERSTANDING THE GENETIC 1192 00:57:40,720 --> 00:57:43,080 PROGRESSION PRESENTS MULTIPLE 1193 00:57:43,080 --> 00:57:45,240 OPPORTUNITIES FOR US IN THE 1194 00:57:45,240 --> 00:57:48,880 LABORATORY THE FIRST IS YOU CAN 1195 00:57:48,880 --> 00:57:52,880 START TO BUILD POWERFUL MOUSE 1196 00:57:52,880 --> 00:58:03,520 MODELS. 1197 00:58:03,520 --> 00:58:07,000 THE NF 1 MOUSE CAN COPY THIS AND 1198 00:58:07,000 --> 00:58:09,000 THEY'VE KNOCKED IT OUT AT 1199 00:58:09,000 --> 00:58:09,720 MULTIPLE TIME POINTS IN 1200 00:58:09,720 --> 00:58:10,280 DIFFERENT CELLS ACROSS THE 1201 00:58:10,280 --> 00:58:16,800 MOUSE. 1202 00:58:16,800 --> 00:58:19,280 DO THEY MATCH WHAT WE SEE IN THE 1203 00:58:19,280 --> 00:58:19,560 PATIENTS? 1204 00:58:19,560 --> 00:58:25,480 YOU CAN SEE THERE'S MULTIPLE NF 1205 00:58:25,480 --> 00:58:28,480 1 MOUSE MODELS. 1206 00:58:28,480 --> 00:58:29,680 SOME MAKE PLEXIFORM AND SOME 1207 00:58:29,680 --> 00:58:31,040 MAKE IT IN CERTAIN PARTS OF THE 1208 00:58:31,040 --> 00:58:36,800 BODY AND SOME MAKE OTHER TUMOR 1209 00:58:36,800 --> 00:58:37,000 TYPES. 1210 00:58:37,000 --> 00:58:40,880 IT'S BEEN A POWERFUL TOOL AND A 1211 00:58:40,880 --> 00:58:46,800 KEY FINDING IS TO GET THE 1212 00:58:46,800 --> 00:58:48,000 PLEXIFORM FIBROMAS TO GROW YOU 1213 00:58:48,000 --> 00:58:49,480 HAVE TO KNOCK THEM OUT AT A 1214 00:58:49,480 --> 00:58:54,600 SPECIFIC TIME WINDOW. 1215 00:58:54,600 --> 00:58:56,880 YOU HAVE TO HAVE THE SECOND 1216 00:58:56,880 --> 00:59:01,400 ALLELE LOST IN THE EMBRYONIC 1217 00:59:01,400 --> 00:59:01,800 STATE. 1218 00:59:01,800 --> 00:59:03,720 IT'S A TIMING EFFECT AND 1219 00:59:03,720 --> 00:59:05,040 PROBABLY HAPPENS PRETTY EARLY IN 1220 00:59:05,040 --> 00:59:10,120 THE PATIENTS. 1221 00:59:10,120 --> 00:59:12,400 THIS IS A MODEL USED DEVELOPED 1222 00:59:12,400 --> 00:59:24,720 BY NANCY RATNER'S GROUP SHE HAD 1223 00:59:24,720 --> 00:59:27,280 A DEVELOPMENTALLY RESTRICTED 1224 00:59:27,280 --> 00:59:29,360 GENE DRIVING AND LINKED TO THE 1225 00:59:29,360 --> 00:59:41,600 LOSS OF NF 1 SO OWN THE SCHWANN 1226 00:59:41,600 --> 00:59:44,080 CELLS STARTED TO DEVELOP TUMORS 1227 00:59:44,080 --> 00:59:47,560 AND THEY'RE SIMILAR TO THE HUMAN 1228 00:59:47,560 --> 00:59:48,880 TUMORS. 1229 00:59:48,880 --> 00:59:50,960 YOU CAN SEE WHAT THE WILD TYPE 1230 00:59:50,960 --> 00:59:58,720 SPINAL CORD AND PERATIVAAL -- 1231 00:59:58,720 --> 01:00:01,680 PERIPHERAL NERVES LOOK LIKE AND 1232 01:00:01,680 --> 01:00:05,800 YOU SEE THESE BIG BENIGN TUMORS 1233 01:00:05,800 --> 01:00:08,720 AND SOME HAVE HYPERPIGMENTATION 1234 01:00:08,720 --> 01:00:19,840 SIMILAR TO THE HUMAN CONDITION. 1235 01:00:19,840 --> 01:00:22,320 WE DISCOVERED MEK INHIBITORS 1236 01:00:22,320 --> 01:00:23,320 IMPORTANT AND IF YOU HAVE A 1237 01:00:23,320 --> 01:00:26,880 MOUSE MODEL YOU CAN RUN THE 1238 01:00:26,880 --> 01:00:31,080 EXPERIMENTS IN THE MOUSE AND 1239 01:00:31,080 --> 01:00:36,280 TAKE THEM TO THE CLINICAL TRIAL. 1240 01:00:36,280 --> 01:00:43,080 YOU CAN SEE IT'S TREATED AND YOU 1241 01:00:43,080 --> 01:00:46,280 CAN TREAT WITH DIFFERENT DOSES 1242 01:00:46,280 --> 01:00:47,440 OF THE DRUG. 1243 01:00:47,440 --> 01:00:51,440 THIS IS A MEK INHIBITOR CALLED 1244 01:00:51,440 --> 01:00:54,000 PD AND YOU SEE THE PLEXIFORMS 1245 01:00:54,000 --> 01:00:56,040 CONTINUE TO GROW IN THE MOUSE 1246 01:00:56,040 --> 01:00:58,640 AND IF YOU HAVE MORE DOSES OF 1247 01:00:58,640 --> 01:01:01,640 THE MEK INHIBITOR YOU HAVE A 1248 01:01:01,640 --> 01:01:02,840 SHRINKAGE OF THE TUMORS. 1249 01:01:02,840 --> 01:01:04,160 THIS IS POWERFUL. 1250 01:01:04,160 --> 01:01:07,080 NOW YOU CAN IMAGINE ALL THE 1251 01:01:07,080 --> 01:01:08,720 FAILED CLINICAL TRIALS WHAT IF 1252 01:01:08,720 --> 01:01:11,120 YOU HAD THE RIGHT MODEL YOU CAN 1253 01:01:11,120 --> 01:01:12,160 TEST THEM IN THE LABORATORY 1254 01:01:12,160 --> 01:01:23,880 BEFORE GIVING THEM TO PATIENTS? 1255 01:01:23,880 --> 01:01:26,160 AND THE TUMOR SUPPRESSER LOSS 1256 01:01:26,160 --> 01:01:27,520 COMES AFTER THE NF 1 LOSS AND 1257 01:01:27,520 --> 01:01:29,880 YOU CAN MAKE A MOUSE THAT MODELS 1258 01:01:29,880 --> 01:01:33,640 THAT. 1259 01:01:33,640 --> 01:01:36,480 IN THE RIGHT PANEL WE'RE SHOWING 1260 01:01:36,480 --> 01:01:38,240 SHOWING A MOUSE MODEL AT THE 1261 01:01:38,240 --> 01:01:44,240 INDIANA UNIVERSITY AND WE'RE 1262 01:01:44,240 --> 01:01:48,920 MIRRORING SIMILARLY BY KNOWING 1263 01:01:48,920 --> 01:01:51,880 THE GENETIC HITS IN THE HUMAN 1264 01:01:51,880 --> 01:01:56,640 ALOUZ US -- ALLOWS US TO BUILD 1265 01:01:56,640 --> 01:01:58,200 MOUSE MODELS AND IS A POWERFUL 1266 01:01:58,200 --> 01:02:00,920 TOOL BUT ONLY COME ONLINE 1267 01:02:00,920 --> 01:02:02,920 RECENTLY. 1268 01:02:02,920 --> 01:02:07,760 THE PROGRESS MADE IN THE EARLY 1269 01:02:07,760 --> 01:02:09,800 PLEXIFORM TRIALS WE CAN MAKE 1270 01:02:09,800 --> 01:02:11,760 ATYPICAL NEUROFIBROMAS. 1271 01:02:11,760 --> 01:02:16,160 ON THE FAR END OF THE SPECTRUM 1272 01:02:16,160 --> 01:02:29,720 IS THE BAD MALIGNANT PLAYERS. 1273 01:02:29,720 --> 01:02:32,880 USING A MOUSE MODEL WITH LOSS OF 1274 01:02:32,880 --> 01:02:39,080 NF 1 AND TP53 ANOTHER TUMOR 1275 01:02:39,080 --> 01:02:50,680 SUPPRESSER WE SEE AND YOU CAN 1276 01:02:50,680 --> 01:02:52,600 TEST DIFFERENT DRUGS OR 1277 01:02:52,600 --> 01:02:53,240 COMBINATIONS IN THE MODEL THAT 1278 01:02:53,240 --> 01:03:00,920 MATCHES THE HUMAN CONDITION. 1279 01:03:00,920 --> 01:03:03,440 THERE'S A MEK INHIBITER AND WHEN 1280 01:03:03,440 --> 01:03:07,080 YOU COMBINE THOSE THINGS YOU GET 1281 01:03:07,080 --> 01:03:08,760 SOME SYNERGY. 1282 01:03:08,760 --> 01:03:12,880 IF YOU USE THE MEK INHIBITOR IN 1283 01:03:12,880 --> 01:03:14,960 THE MPNST IT DOESN'T REALLY 1284 01:03:14,960 --> 01:03:18,880 RESPOND AT ALL AND WE SEE THAT 1285 01:03:18,880 --> 01:03:20,760 IN THE PATIENTS. 1286 01:03:20,760 --> 01:03:21,440 INTERESTING CORRELATION BETWEEN 1287 01:03:21,440 --> 01:03:34,200 THE CLINIC AND LABORATORY. 1288 01:03:34,200 --> 01:03:36,200 IS A CLINICAL TRIAL AND WE WERE 1289 01:03:36,200 --> 01:03:38,360 A PARTICIPATING SITE AND WERE 1290 01:03:38,360 --> 01:03:39,520 RECENTLY PUSH THIS THROUGH TO 1291 01:03:39,520 --> 01:03:40,680 PATIENTS FOLLOWING THE MODEL. 1292 01:03:40,680 --> 01:03:48,920 AND WE ALWAYS HAVE OUR EYE ON 1293 01:03:48,920 --> 01:03:50,680 THE NEXT THING AND WHAT IS 1294 01:03:50,680 --> 01:03:52,920 LIKELY TO WORK AND IT'S USED TO 1295 01:03:52,920 --> 01:03:57,400 SHOW THIS, THERE'S A COMBINATION 1296 01:03:57,400 --> 01:04:04,840 OF TWO INHIBITERS A MEK AND 1297 01:04:04,840 --> 01:04:10,360 BROMO DOMAIN INHIBITOR. 1298 01:04:10,360 --> 01:04:13,920 IT'S INTERESTING IS THIS 1299 01:04:13,920 --> 01:04:15,320 UNLEASHED AN IMMUNE RESPONSE 1300 01:04:15,320 --> 01:04:18,920 WHEN YOU ADDED THIS TO A PD 1301 01:04:18,920 --> 01:04:24,560 CHECKPOINT INHIBITOR. 1302 01:04:24,560 --> 01:04:35,480 THIS REALLY WHEN YOU UNLEASH 1303 01:04:35,480 --> 01:04:37,720 THIS YOU GET THE INHIBITOR AND 1304 01:04:37,720 --> 01:04:43,120 LET'S TAKE THIS IN THE CLINICAL 1305 01:04:43,120 --> 01:04:44,320 TRIAL. 1306 01:04:44,320 --> 01:04:46,360 WHAT THE MOUSE WAS TEACHING US 1307 01:04:46,360 --> 01:04:51,000 WE CAN TAKE THAT BACK TO THE 1308 01:04:51,000 --> 01:04:51,440 HUMAN. 1309 01:04:51,440 --> 01:04:52,920 THAT'S OUR MODEL FOR HOW IT WILL 1310 01:04:52,920 --> 01:04:59,120 WORK. 1311 01:04:59,120 --> 01:05:00,920 OUR PATIENT MADE THE POINT, I 1312 01:05:00,920 --> 01:05:03,880 DON'T WANT TO GET MPNSTAL ALL. 1313 01:05:03,880 --> 01:05:06,320 IF I CAN GET ONE THING MAYBE 1314 01:05:06,320 --> 01:05:10,080 IT'S TO STOP THE PROGRESSION. 1315 01:05:10,080 --> 01:05:14,680 YOU HEARD SOME OF DR. WIDEMANN'S 1316 01:05:14,680 --> 01:05:19,960 STRATEGIES, LET'S DO SURGERY 1317 01:05:19,960 --> 01:05:23,840 WHEN WE SEE THEM AND MEDICAL 1318 01:05:23,840 --> 01:05:25,160 THERAPIES TO TREAT THESE 1319 01:05:25,160 --> 01:05:26,080 NEUROFIBROMAS BEFORE THEY MAKE 1320 01:05:26,080 --> 01:05:30,440 THE JUMP. 1321 01:05:30,440 --> 01:05:36,560 ONE THING WE'VE HAD SUCCESS OVER 1322 01:05:36,560 --> 01:05:39,000 IN RECENT TIMES AND PREDICT WHEN 1323 01:05:39,000 --> 01:05:40,960 THE MALIGNANT TRANSFORMATIONS 1324 01:05:40,960 --> 01:05:42,360 ARE HAPPENING, WOULDN'T THAT BE 1325 01:05:42,360 --> 01:05:50,080 A USEFUL TOOL? 1326 01:05:50,080 --> 01:05:51,400 IN SOME WAYS THE TECHNOLOGY HAS 1327 01:05:51,400 --> 01:05:52,920 ADVANCED TO THE POINT WHERE WE 1328 01:05:52,920 --> 01:05:58,520 CAN START TO DO THIS. 1329 01:05:58,520 --> 01:06:00,800 DR. WIDEMANN SHOWED RIGHT NOW WE 1330 01:06:00,800 --> 01:06:02,880 DIAGNOSIS THESE CLINICALLY. 1331 01:06:02,880 --> 01:06:04,480 THE PATIENT WILL SAY IT'S 1332 01:06:04,480 --> 01:06:06,960 ACTUALLY MORE PAINFUL. 1333 01:06:06,960 --> 01:06:08,760 LET'S TAKE A DEEPER LOOK AT THAT 1334 01:06:08,760 --> 01:06:15,080 OR SCAN HEAD TO TOE WITH AN MRI 1335 01:06:15,080 --> 01:06:15,680 EVERY YEAR. 1336 01:06:15,680 --> 01:06:20,880 YOU CAN IMAGINE IT'S NOT 1337 01:06:20,880 --> 01:06:23,360 PARTICULARLY SENSITIVE OR 1338 01:06:23,360 --> 01:06:24,800 SPECIFIC BECAUSE WE THINK 1339 01:06:24,800 --> 01:06:28,040 THEY'RE DEVELOPING WITHIN THE 1340 01:06:28,040 --> 01:06:30,640 BIGGER PLEXIFORM FIBROMA AND WE 1341 01:06:30,640 --> 01:06:32,640 CAN STICK A NEEDLE INTO EVERY 1342 01:06:32,640 --> 01:06:34,040 AREA WE'RE CONCERNED AND LOOK AT 1343 01:06:34,040 --> 01:06:35,840 THE TISSUE BUT IT HAS 1344 01:06:35,840 --> 01:06:37,160 SIGNIFICANT MORBIDITY AS WELL. 1345 01:06:37,160 --> 01:06:39,240 YOU DON'T WANT TO DO A LOT OF 1346 01:06:39,240 --> 01:06:42,160 PROCEDURES IN THE LARGE BENIGN 1347 01:06:42,160 --> 01:06:50,360 TUMORS ESPECIALLY FOR NO REASON. 1348 01:06:50,360 --> 01:06:52,920 YOU CAN STICK THE NEEDLE TO THE 1349 01:06:52,920 --> 01:06:58,760 RIGHT OR LEFT AND MISS A 1350 01:06:58,760 --> 01:06:59,080 DIAGNOSIS. 1351 01:06:59,080 --> 01:07:02,200 WHAT WE'VE DONE IS SAY WHAT IF 1352 01:07:02,200 --> 01:07:04,120 WE LOOK AT PLASMA TO SEE 1353 01:07:04,120 --> 01:07:14,360 EVIDENCE OF THE CHANGES. 1354 01:07:14,360 --> 01:07:19,480 THIS HAS BEEN LED BY MY GROUP 1355 01:07:19,480 --> 01:07:32,880 AND IT SEEMS LIKE ANUPLOITY AND 1356 01:07:32,880 --> 01:07:35,160 IN TUMORS YOU GET GAINS AND 1357 01:07:35,160 --> 01:07:40,880 LOSSES OF CHROMOSOMES. 1358 01:07:40,880 --> 01:07:57,920 THE TUMOR CAN ADD DEF AND IF YOU 1359 01:07:57,920 --> 01:08:00,880 LOOK AT THE MPNST THIS INCREASE 1360 01:08:00,880 --> 01:08:01,240 EXPONENTIALLY. 1361 01:08:01,240 --> 01:08:03,880 THEY'RE BECOMING MORE AND MORE A 1362 01:08:03,880 --> 01:08:05,040 FEATURE OF THE MPNST. 1363 01:08:05,040 --> 01:08:12,080 SO WE SAID OKAY WE NEED A BLOOD 1364 01:08:12,080 --> 01:08:20,000 TEST TO DETECT THE ANEUPLOID 1365 01:08:20,000 --> 01:08:22,520 EVENTS AND TOOK PATIENTS THAT 1366 01:08:22,520 --> 01:08:38,960 HAD BENIGN AND MALIGNANT TUMORS. 1367 01:08:38,960 --> 01:08:40,880 AND WE TAKE THE PLASMA AND SPIN 1368 01:08:40,880 --> 01:08:44,040 IT DOWN AND DO WHOLE GENOME 1369 01:08:44,040 --> 01:08:44,320 SEQUENCING. 1370 01:08:44,320 --> 01:08:46,560 WE LOOK AT SHALLOW SEQUENCING 1371 01:08:46,560 --> 01:08:52,760 ACROSS THE GENOME. 1372 01:08:52,760 --> 01:08:56,040 IT ALLOWS TO PREDICT THE 1373 01:08:56,040 --> 01:08:56,920 ANEUPLOIDY CHANGES AND CORRELATE 1374 01:08:56,920 --> 01:09:00,680 THIS WITH THE FINDINGS AND 1375 01:09:00,680 --> 01:09:04,480 ANOTHER KEY FEATURE IS THE 1376 01:09:04,480 --> 01:09:05,400 CELL-FREE DNA FRAGMENT SELECTION 1377 01:09:05,400 --> 01:09:06,840 I'LL TOUCH ON. 1378 01:09:06,840 --> 01:09:08,400 THIS IS WHAT THIS LOOKS LIKE AND 1379 01:09:08,400 --> 01:09:09,560 TO ME IS STRIKE. 1380 01:09:09,560 --> 01:09:12,800 IF YOU SEQUENCE THE TUMOR DNA, 1381 01:09:12,800 --> 01:09:17,720 NORMALLY THIS SHOULD BE RIGHT 1382 01:09:17,720 --> 01:09:20,880 ALONG THE DIPLOID GENOME. 1383 01:09:20,880 --> 01:09:23,400 HERE'S THE PATIENT'S GERM LINE 1384 01:09:23,400 --> 01:09:27,720 DNA DOWN HERE. 1385 01:09:27,720 --> 01:09:32,280 NICE AND FLAT. 1386 01:09:32,280 --> 01:09:35,080 YOU SEE CHROMOSOME AND 2 AND IF 1387 01:09:35,080 --> 01:09:39,000 YOU SEQUENCE THE DNA FROM THE 1388 01:09:39,000 --> 01:09:40,880 PLASMA, SURE ENOUGH YOU CAN SEE 1389 01:09:40,880 --> 01:09:43,120 THE TUMOR DNA SHED IN THE 1390 01:09:43,120 --> 01:09:44,880 BLOODSTREAM AND YOU CAN SEE IT 1391 01:09:44,880 --> 01:09:48,880 NICELY MIRRORS THE CHANGES IF 1392 01:09:48,880 --> 01:09:53,920 YOU LOOK AT THE TUMOR. 1393 01:09:53,920 --> 01:09:55,200 NOW WE HAVE A BIOMARKER AND IF 1394 01:09:55,200 --> 01:09:57,600 YOU GIVE A PATIENT THERAPY AND 1395 01:09:57,600 --> 01:09:59,480 START TO SHRINK THE TUMOR YOU 1396 01:09:59,480 --> 01:10:01,640 START TO SEE IT GO AWAY. 1397 01:10:01,640 --> 01:10:03,240 THAT'S A USEFUL TOOL CLINICALLY 1398 01:10:03,240 --> 01:10:06,240 BECAUSE NOW YOU CAN FOLLOW THE 1399 01:10:06,240 --> 01:10:08,000 PATIENT OR FOLLOW THE PATIENT IN 1400 01:10:08,000 --> 01:10:11,120 THE BENIGN STATE AND LOOK FOR 1401 01:10:11,120 --> 01:10:12,720 THESE CHANGES AND IF YOU SEE 1402 01:10:12,720 --> 01:10:14,520 THESE CHANGES YOU MAY WANT TO BE 1403 01:10:14,520 --> 01:10:20,880 WORRIED IT'S TRANSFORMED 1404 01:10:20,880 --> 01:10:21,880 SOMEWHERE. 1405 01:10:21,880 --> 01:10:23,480 A POWERFUL ADJUNCT WITH US THIS 1406 01:10:23,480 --> 01:10:24,920 DISCOVERY THE SIZE OF THE 1407 01:10:24,920 --> 01:10:26,680 GENOMIC FRAGMENTS WE WERE 1408 01:10:26,680 --> 01:10:28,800 FINDING IF IT CAME FROM THE 1409 01:10:28,800 --> 01:10:30,160 TUMOR, WERE A LITTLE BIT 1410 01:10:30,160 --> 01:10:30,680 SHORTER. 1411 01:10:30,680 --> 01:10:32,920 THIS WAS SEEN IN MULTIPLE TUMOR 1412 01:10:32,920 --> 01:10:36,240 TYPES NOW WHERE THE ASSUMER 1413 01:10:36,240 --> 01:10:38,560 SEEMS TO SHED SMALLER FRAGMENTS 1414 01:10:38,560 --> 01:10:40,280 OF DNA AND NOBODY'S QUITE CLEAR 1415 01:10:40,280 --> 01:10:44,480 WHERE IT HAPPENS BUT IS A 1416 01:10:44,480 --> 01:10:45,320 RECURRENT FEATURE IN TUMOR TYPES 1417 01:10:45,320 --> 01:10:47,120 AND WE CAN FILTER THIS AND MAKE 1418 01:10:47,120 --> 01:10:51,920 IT A BETTER TEST BY JUST LOOKING 1419 01:10:51,920 --> 01:10:59,280 AT AT AN AREA OF SEQUENCING READ 1420 01:10:59,280 --> 01:11:04,000 SPECIFIC LENGTH ENRICHED FOR THE 1421 01:11:04,000 --> 01:11:06,760 TUMOR AND IF YOU STARTED TO LOOK 1422 01:11:06,760 --> 01:11:10,800 AT THIS COMPARED TO THINGS THAT 1423 01:11:10,800 --> 01:11:12,880 WE NORMALLY DO IN THE CLINIC 1424 01:11:12,880 --> 01:11:15,320 LINE ANATOMIC MRI WITH A 1425 01:11:15,320 --> 01:11:17,760 SPECIFICITY OF 61% WE WERE JUST 1426 01:11:17,760 --> 01:11:20,880 AS GOOD IF NOT A LITTLE BIT 1427 01:11:20,880 --> 01:11:27,800 BETTER USING OUR CELL-FREE 1428 01:11:27,800 --> 01:11:32,280 GENOME SEQUENCES. 1429 01:11:32,280 --> 01:11:33,680 WE CONTINUE TO REFINE THIS BUT 1430 01:11:33,680 --> 01:11:36,920 IT'S AN EXCITING WAY YOU CAN 1431 01:11:36,920 --> 01:11:39,640 IMAGINE INCORPORATING THIS INTO 1432 01:11:39,640 --> 01:11:42,840 YOUR CLINIC WHERE YOU HAVE 1433 01:11:42,840 --> 01:11:44,520 MULTIPLE F1 PATIENTS. 1434 01:11:44,520 --> 01:11:48,520 INSTEAD OF SCANNING THEM HEAD TO 1435 01:11:48,520 --> 01:11:54,240 TOE YOU WOULD GET A BLOOD TEST 1436 01:11:54,240 --> 01:11:59,080 AND LOOK FOR CHANGES. 1437 01:11:59,080 --> 01:12:01,480 THE CELL-FREE DNA ASSAY WAS 1438 01:12:01,480 --> 01:12:06,240 PICKING THIS UP BEFORE THE 1439 01:12:06,240 --> 01:12:11,440 IMAGING AND YOU CAN ONLY DO 1440 01:12:11,440 --> 01:12:14,520 IMAGING SO OFTEN BUT CAN DO A 1441 01:12:14,520 --> 01:12:15,680 BROOD TEST AND THIS HAS HUGE 1442 01:12:15,680 --> 01:12:19,760 POTENTIAL IN THE PATIENTS THAT 1443 01:12:19,760 --> 01:12:22,560 HAVE A GERM LINE PREDISPOSITION 1444 01:12:22,560 --> 01:12:25,000 WHERE YOU'RE LIKELY TO GET A 1445 01:12:25,000 --> 01:12:28,880 TUMOR AT SOME POINT IN YOUR 1446 01:12:28,880 --> 01:12:29,560 LIFE. 1447 01:12:29,560 --> 01:12:31,160 THIS ASSAY MIRRORED THE 1448 01:12:31,160 --> 01:12:32,880 TREATMENT COURSE FOR THE 1449 01:12:32,880 --> 01:12:33,120 PATIENT. 1450 01:12:33,120 --> 01:12:38,600 IF YOU GAVE A SUCCESSFUL 1451 01:12:38,600 --> 01:12:47,720 TREATMENT, THE CELL-FREE DNA 1452 01:12:47,720 --> 01:12:49,160 ASSAY WOULD COME UP AND IF YOU 1453 01:12:49,160 --> 01:12:51,480 DON'T WAIT FOR THE PATIENT TO 1454 01:12:51,480 --> 01:12:52,480 BLOW THROUGH WHATEVER THERAPY 1455 01:12:52,480 --> 01:12:55,120 YOU'RE GIVING THEM YOU CAN FOL 1456 01:12:55,120 --> 01:12:59,280 THEM AND SEE HOW THEY'RE DOING 1457 01:12:59,280 --> 01:13:04,880 AND PROGRESSING AND WOULD ALLOW 1458 01:13:04,880 --> 01:13:15,840 US TO MAYBE TRI TATE THE THERAPY 1459 01:13:15,840 --> 01:13:19,120 AND THERE'S TUMOR CELLULAR 1460 01:13:19,120 --> 01:13:26,280 GENEITY -- GEN AITY AND WE WOULD 1461 01:13:26,280 --> 01:13:28,200 EXTRACT THINGS LIKE THE DNA AND 1462 01:13:28,200 --> 01:13:34,880 RNA AND THAT WOULD BE AVERAGED 1463 01:13:34,880 --> 01:13:35,240 OUT. 1464 01:13:35,240 --> 01:13:38,200 AND THAT'S THE FRUIT SALAD 1465 01:13:38,200 --> 01:13:48,920 APPROACH TO SEQUENCING AND WE'RE 1466 01:13:48,920 --> 01:13:54,200 STARTING TO DO SINGLE CELL 1467 01:13:54,200 --> 01:13:55,480 SEQUENCING AND YOU CAN TEASE OUT 1468 01:13:55,480 --> 01:13:56,880 POPULATIONS AND STUDY THOSE IN 1469 01:13:56,880 --> 01:14:05,640 DETAIL. 1470 01:14:05,640 --> 01:14:15,480 THESE ARE MASSIVE TUMORS AND YOU 1471 01:14:15,480 --> 01:14:20,440 SEE A PLEXIFORM NEUROFIBROMA BUT 1472 01:14:20,440 --> 01:14:21,080 WAS COMPLAINING OF PAIN IN THE 1473 01:14:21,080 --> 01:14:23,080 UPPER PART OF THE TUMOR. 1474 01:14:23,080 --> 01:14:41,280 YOU CAN SEE THE DISTINCT NOJ -- 1475 01:14:41,280 --> 01:14:43,160 NODULEAR AREA AND YOU CAN 1476 01:14:43,160 --> 01:14:48,760 IMAGINE IF YOU DID BIOPSIES IN 1477 01:14:48,760 --> 01:14:49,680 MULTIPLE PLACES YOU'D GET 1478 01:14:49,680 --> 01:14:50,280 DIFFERENT ANSWERS. 1479 01:14:50,280 --> 01:14:53,120 IT'S A BENEFIT OF WORKING AT THE 1480 01:14:53,120 --> 01:14:54,200 NIH CLINICAL CENTER. 1481 01:14:54,200 --> 01:14:57,120 WE CAN ENROLL THEM AND STUDY 1482 01:14:57,120 --> 01:15:04,680 TUMORS IN DEPTH ACROSS THEM. 1483 01:15:04,680 --> 01:15:08,080 AND WHAT YOU SEE AT EVERY STAGE 1484 01:15:08,080 --> 01:15:12,000 OF THESE TUMORS THERE ARE 1485 01:15:12,000 --> 01:15:15,240 DISTINCT POPULATIONS OF CELLS 1486 01:15:15,240 --> 01:15:16,640 THERE'S IMMUNE CELLS AND TUMOR 1487 01:15:16,640 --> 01:15:19,200 CELLS AND STROMAL CELLS MAKING 1488 01:15:19,200 --> 01:15:24,960 THIS THICK PINK MATRIX IN THE 1489 01:15:24,960 --> 01:15:29,840 SLIDES. 1490 01:15:29,840 --> 01:15:30,800 THEORY IS EACH CELL POPULATION 1491 01:15:30,800 --> 01:15:32,240 CONTRIBUTES TO THE TUMOR'S 1492 01:15:32,240 --> 01:15:32,480 GROWTH. 1493 01:15:32,480 --> 01:15:36,960 IT'S THE MICROENVIRONMENT THAT 1494 01:15:36,960 --> 01:15:40,960 ALLOWS THE TUMOR TO AGAIN TO 1495 01:15:40,960 --> 01:15:44,920 GROW AND YOU CAN IMAGINE EVERY 1496 01:15:44,920 --> 01:15:48,920 ONE OF THOSE CELL POPULATIONS 1497 01:15:48,920 --> 01:15:53,400 BECOMES A POTENTIAL THERAPY. 1498 01:15:53,400 --> 01:15:55,160 AND IMMUNE THERAPY IS BECOMING 1499 01:15:55,160 --> 01:15:57,960 MORE AND MORE SUCCESSFUL. 1500 01:15:57,960 --> 01:16:00,280 IMAGINE CHARACTERIZING THE T 1501 01:16:00,280 --> 01:16:02,280 CELLS WITHIN THE TUMORS BECOMES 1502 01:16:02,280 --> 01:16:02,880 AN IMMEDIATE THERAPEUTIC 1503 01:16:02,880 --> 01:16:04,720 POTENTIAL FOR THE MACROPHAGES 1504 01:16:04,720 --> 01:16:14,080 PRESENT IN THE TUMORS. 1505 01:16:14,080 --> 01:16:20,360 AND YOU HAVE TO UNDERSTAND THE 1506 01:16:20,360 --> 01:16:20,880 COMPLEX ENVIRONMENT TO 1507 01:16:20,880 --> 01:16:24,600 UNDERSTAND WHY YOUR TUMOR IS 1508 01:16:24,600 --> 01:16:24,960 PROGRESSING. 1509 01:16:24,960 --> 01:16:30,160 WHY HAS THE MEK INHIBITOR ONLY 1510 01:16:30,160 --> 01:16:32,960 SHRUNK IT BY 20% AND THOSE ARE 1511 01:16:32,960 --> 01:16:34,440 KEY QUESTIONS WE'RE STARTING TO 1512 01:16:34,440 --> 01:16:34,960 ANSWER NOW. 1513 01:16:34,960 --> 01:16:44,080 YOU CAN SEE IN THE TUMORS THE 1514 01:16:44,080 --> 01:16:47,680 SMALL IMMUNE CELLS AND THE TUMOR 1515 01:16:47,680 --> 01:17:11,960 CELLS ARE ELONGATED NUCLEI HERE. 1516 01:17:11,960 --> 01:17:16,480 AND THE CURRENT BASIC 1517 01:17:16,480 --> 01:17:19,120 UNDERSTANDING OF THIS IS THERE'S 1518 01:17:19,120 --> 01:17:28,840 A NEOPLASTIC SCHWANN CELL AND 1519 01:17:28,840 --> 01:17:30,800 THIS INTERN FEEDS BACK AND 1520 01:17:30,800 --> 01:17:33,440 DELIVERS GROWTH FACTORS BACK TO 1521 01:17:33,440 --> 01:17:50,080 THE NEOPLASTIC SCHWANN CELL AND 1522 01:17:50,080 --> 01:17:52,200 THIS IS KEY FOR THE NEXT SET OF 1523 01:17:52,200 --> 01:17:53,720 THERAPIES FOR THE PATIENTS AND 1524 01:17:53,720 --> 01:17:56,160 WHAT WE'VE WORKED ON IN MY 1525 01:17:56,160 --> 01:17:58,600 LABORATORY LED BY A TALENTED 1526 01:17:58,600 --> 01:18:01,920 POST-DOC AND THE IDEA IS WE'LL 1527 01:18:01,920 --> 01:18:04,840 CREATE A SINGLE CELL ATLAS OF 1528 01:18:04,840 --> 01:18:07,560 ALL THE CELL TYPES WITHIN THE NF 1529 01:18:07,560 --> 01:18:10,200 1 NERVE TUMORS. 1530 01:18:10,200 --> 01:18:11,480 HAVING THE NATURAL HISTORY AND 1531 01:18:11,480 --> 01:18:16,680 CLINICAL STUDY WE'RE ABLE TO 1532 01:18:16,680 --> 01:18:22,360 COLLECT PATIENTS SEQUENCE BY 1533 01:18:22,360 --> 01:18:25,000 SINGLE CELL SEQUENCING AND EVERY 1534 01:18:25,000 --> 01:18:28,920 DOT REPRESENTS THE GENE 1535 01:18:28,920 --> 01:18:29,480 EXPRESSION PROFILE OF AN 1536 01:18:29,480 --> 01:18:35,680 INDIVIDUAL CELL. 1537 01:18:35,680 --> 01:18:39,480 THIS COMES FROM 56 UNIQUE TUMOR 1538 01:18:39,480 --> 01:18:40,920 SAMPLES AND 49 INDIVIDUAL TUMORS 1539 01:18:40,920 --> 01:18:48,880 AND 500,000 SINGLE CELLS. 1540 01:18:48,880 --> 01:18:50,240 THE REWARDING THING OF THE 1541 01:18:50,240 --> 01:18:53,280 EXPERIMENTS IS TO START TO 1542 01:18:53,280 --> 01:18:56,880 DEFINE CELL POPULATIONS BASED ON 1543 01:18:56,880 --> 01:19:01,160 THE GENE EXPRESSION PROFILING. 1544 01:19:01,160 --> 01:19:05,800 YOU CAN SEE HERE'S THE MALIGNANT 1545 01:19:05,800 --> 01:19:07,080 SCHWANN CELL. 1546 01:19:07,080 --> 01:19:14,640 HERE'S ALL THE LYMPHOID CELLS 1547 01:19:14,640 --> 01:19:20,680 BEEN THE BIG MAP AND THE 1548 01:19:20,680 --> 01:19:21,360 FIBROBLAST. 1549 01:19:21,360 --> 01:19:24,920 YOU CAN START TO SUB CLUSTER 1550 01:19:24,920 --> 01:19:31,080 WITHIN INDIVIDUAL GROUPS. 1551 01:19:31,080 --> 01:19:34,840 YOU CAN LOOK AT ALL THE CELLS 1552 01:19:34,840 --> 01:19:38,160 FROM A PATIENT WITH A PLEXIFORM 1553 01:19:38,160 --> 01:19:43,120 NEUROFIBROPLA OR MPNST AND SEE 1554 01:19:43,120 --> 01:19:47,440 THE VERY DIFFERENT PROFILES AND 1555 01:19:47,440 --> 01:19:48,880 IF YOU SUMMARIZE THIS THE 1556 01:19:48,880 --> 01:19:54,600 OBVIOUS ONE IS THIS BIG PINK 1557 01:19:54,600 --> 01:20:00,640 REGION GROUP THE TUMOR CELLS. 1558 01:20:00,640 --> 01:20:07,200 NOT SURPRISE IING THERE'S TARGETS 1559 01:20:07,200 --> 01:20:12,240 AND LOOK AT THE CLUSTER ON THE 1560 01:20:12,240 --> 01:20:14,840 FIBROBLAST SPECIFIC TO THE 1561 01:20:14,840 --> 01:20:15,040 MPNST. 1562 01:20:15,040 --> 01:20:20,480 AGAIN THIS OPENS UP NEW IDEAS 1563 01:20:20,480 --> 01:20:26,120 AND WAYS TO ENGINEER AND IT 1564 01:20:26,120 --> 01:20:31,080 STRUCK ME HOW SIMILAR IT WAS. 1565 01:20:31,080 --> 01:20:32,200 YOU GET THE PURPLE GROUP AND 1566 01:20:32,200 --> 01:20:36,360 THAT'S THE TUMOR CELL POPULATION 1567 01:20:36,360 --> 01:20:38,680 AND CONTRACTION OF THE MYELOID 1568 01:20:38,680 --> 01:20:39,520 IMMUNE CELLS. 1569 01:20:39,520 --> 01:20:53,840 THOSE TWO THE ATYPICAL AND AND 1570 01:20:53,840 --> 01:20:56,040 I'M A CANCER CELL BIOLOGIST AND 1571 01:20:56,040 --> 01:20:59,080 I'M INTERESTED IN THE MALIGNANT 1572 01:20:59,080 --> 01:21:00,600 TRANSFORMATION OF THE CANCER 1573 01:21:00,600 --> 01:21:02,080 CELLS AND YOU CAN FOLLOW THEM 1574 01:21:02,080 --> 01:21:05,000 AND LOOK AT THE SINGLE-CELL 1575 01:21:05,000 --> 01:21:08,280 RESOLUTION LEVEL AND LOOK AT THE 1576 01:21:08,280 --> 01:21:09,600 GENE EXPRESSION PROFILE AND 1577 01:21:09,600 --> 01:21:12,000 THOSE DROPPING OUT OF THE 1578 01:21:12,000 --> 01:21:14,600 TYPICAL LESION AND AS IT BECOMES 1579 01:21:14,600 --> 01:21:16,560 AN MPNST. 1580 01:21:16,560 --> 01:21:19,080 ONE THING THAT STRUCK US OUT OF 1581 01:21:19,080 --> 01:21:28,280 THE GATE IF YOU TOOK THE SCHWANN 1582 01:21:28,280 --> 01:21:32,920 CELLS REPRESENTS THE GENE 1583 01:21:32,920 --> 01:21:34,680 EXPRESSION PROFILE. 1584 01:21:34,680 --> 01:21:38,120 WITH THE EXPERIMENT YOU CAN SEE 1585 01:21:38,120 --> 01:21:41,760 THERE'S A PLEXIFORM SIDE OF THE 1586 01:21:41,760 --> 01:21:48,880 SCHWANN AND CELL GROUP AND THAT 1587 01:21:48,880 --> 01:21:59,840 CHANGE REPRESENTS A BASIC 1588 01:21:59,840 --> 01:22:02,240 UNDERSTANDING AND THERE'S 1589 01:22:02,240 --> 01:22:02,480 CDKNTA. 1590 01:22:02,480 --> 01:22:04,480 THERE'S A FINDING THAT DIDN'T 1591 01:22:04,480 --> 01:22:08,880 MAKE SENSE OUT OF THE GATE. 1592 01:22:08,880 --> 01:22:12,880 IN THE PLEXIFORM AND IN THE 1593 01:22:12,880 --> 01:22:16,880 ATYPICALS, IT'S REALLY HIGHLY 1594 01:22:16,880 --> 01:22:20,200 EXPRESSED IN FACT'S A BIOMARKER 1595 01:22:20,200 --> 01:22:22,040 OF THE CELLS. 1596 01:22:22,040 --> 01:22:24,360 WE EXPECT IT TO BE GONE AND SURE 1597 01:22:24,360 --> 01:22:29,480 ENOUGH IF YOU LOOK AT THE 1598 01:22:29,480 --> 01:22:30,560 ATYPICAL 1599 01:22:30,560 --> 01:22:33,240 ATYPICALS YOU HAVE A LARGE 1600 01:22:33,240 --> 01:22:40,280 NUMBER OF CELLS AND WHAT'S THE 1601 01:22:40,280 --> 01:22:40,680 POPULATION? 1602 01:22:40,680 --> 01:22:41,760 IT COMES DOWN TO THIS 1603 01:22:41,760 --> 01:22:42,400 EXPERIMENT. 1604 01:22:42,400 --> 01:22:44,480 THIS IS ANOTHER UNIQUE POINT 1605 01:22:44,480 --> 01:22:47,480 WHERE THIS RESOLUTION CAN GIVE 1606 01:22:47,480 --> 01:22:54,480 YOU A TARGET. 1607 01:22:54,480 --> 01:22:56,480 THIS IS AGAIN WORK DONE IN 1608 01:22:56,480 --> 01:22:58,760 INDIANA IF YOU TAKE THE SCHWANN 1609 01:22:58,760 --> 01:23:04,480 CELLS AND CULTURE THEM, WHAT YOU 1610 01:23:04,480 --> 01:23:08,880 SEE IS NOT SURPRISING, THE CELLS 1611 01:23:08,880 --> 01:23:12,760 GROW BUT THEY DON'T GROW SUPER 1612 01:23:12,760 --> 01:23:13,000 RAPIDLY. 1613 01:23:13,000 --> 01:23:16,880 THEY GROW A BIT BETTER THAN THE 1614 01:23:16,880 --> 01:23:17,280 WILD TYPE. 1615 01:23:17,280 --> 01:23:20,920 IF YOU STAIN WITH A MARKER OF 1616 01:23:20,920 --> 01:23:27,560 CELLULAR SENESCENCE, THE NF 1 1617 01:23:27,560 --> 01:23:29,520 KNOCKOUT CELLS HAVE A LOT OF 1618 01:23:29,520 --> 01:23:32,920 SENESCEN 1619 01:23:32,920 --> 01:23:35,480 SENESCENCE. 1620 01:23:35,480 --> 01:23:40,280 YOU SEE THIS AT THE mRNA LEVEL 1621 01:23:40,280 --> 01:23:41,360 AND YOU CAN SEE THIS AT THE 1622 01:23:41,360 --> 01:23:56,640 PROTEIN LEVEL AS WELL. 1623 01:23:56,640 --> 01:24:00,960 THIS IS REVOLUTIONIZING HOW TO 1624 01:24:00,960 --> 01:24:03,760 VIEW THIS AND MAYBE THE MOUSE 1625 01:24:03,760 --> 01:24:05,840 MODEL SKIPS A STEP AND MAYBE 1626 01:24:05,840 --> 01:24:06,960 WE'RE MISSING PART OF THE 1627 01:24:06,960 --> 01:24:08,040 PICTURE HERE. 1628 01:24:08,040 --> 01:24:14,600 IF YOU FOLLOW THE CDKN2A LEVEL 1629 01:24:14,600 --> 01:24:20,840 MOVING FROM THE PLEXIFORM OR 1630 01:24:20,840 --> 01:24:23,080 MPNST IT GOES UP AND THEN DOWN. 1631 01:24:23,080 --> 01:24:28,960 I THINK THE MOUSE MODEL SKIPS 1632 01:24:28,960 --> 01:24:32,960 THIS. 1633 01:24:32,960 --> 01:24:36,040 IF YOU LOSE NF 1 AS A SCHWANN 1634 01:24:36,040 --> 01:24:39,600 CELL YOU WANT THE CELL TO STOP 1635 01:24:39,600 --> 01:24:39,840 GROWING. 1636 01:24:39,840 --> 01:24:40,920 THAT'S WHAT IT'S DOING. 1637 01:24:40,920 --> 01:24:44,360 I THINK THESE ARE THE ATYPICALS 1638 01:24:44,360 --> 01:24:48,840 WHERE THEY STOP GROWING AND SIT 1639 01:24:48,840 --> 01:24:51,800 IN PLACE AND HAVE VERY FEW 1640 01:24:51,800 --> 01:24:53,840 MITOSIS AND LOSE SOME CELLULAR 1641 01:24:53,840 --> 01:24:58,080 ARCHITECTURE AND MAY BE NODULAR 1642 01:24:58,080 --> 01:25:02,880 BUT CDKN2A IS INTACT. 1643 01:25:02,880 --> 01:25:04,880 WITHIN THAT A CELL WILL HAVE AN 1644 01:25:04,880 --> 01:25:07,000 EVENT BY THE NUMBER OF CELL 1645 01:25:07,000 --> 01:25:08,840 DIVISIONS IT WILL HAPPEN. 1646 01:25:08,840 --> 01:25:10,160 AND THAT'S THE CELL THAT ALLOWS 1647 01:25:10,160 --> 01:25:14,160 IT TO JUMP OFF THE EDGE AND 1648 01:25:14,160 --> 01:25:15,840 PROGRESSION TOWARDS THE 1649 01:25:15,840 --> 01:25:16,480 MALIGNANCY. 1650 01:25:16,480 --> 01:25:18,680 AGAIN, YOU CAN START TO COME UP 1651 01:25:18,680 --> 01:25:23,160 WITH ALL DIFFERENT IDEAS AND 1652 01:25:23,160 --> 01:25:24,440 QUESTIONS ABOUT WHAT CAUSED THE 1653 01:25:24,440 --> 01:25:25,440 CHANGE AND WHAT'S THE CELL 1654 01:25:25,440 --> 01:25:26,800 TRYING TO DO? 1655 01:25:26,800 --> 01:25:30,120 IS IT TRYING TO ARREST OR 1656 01:25:30,120 --> 01:25:32,120 HAPPENING BECAUSE THE TUMORS ARE 1657 01:25:32,120 --> 01:25:33,520 CONSTRAINED OR SOME CELLULAR 1658 01:25:33,520 --> 01:25:33,800 STRESS. 1659 01:25:33,800 --> 01:25:40,200 COULD WE TRY AND GET RID OF THE 1660 01:25:40,200 --> 01:25:42,000 CDKN2A HIGH CELLS AND PRUNE THEM 1661 01:25:42,000 --> 01:25:45,320 BECAUSE THEY'RE AT RISK OF 1662 01:25:45,320 --> 01:25:46,840 FALLING OFF THE CLIFF AND IS IT 1663 01:25:46,840 --> 01:25:51,000 TRUE ONE CELL OR MAYBE A HANDFUL 1664 01:25:51,000 --> 01:25:55,160 OF CELLS WILL LOSE THAT LOCUS 1665 01:25:55,160 --> 01:25:56,920 AND THAT'S THE PROGRESSION THAT 1666 01:25:56,920 --> 01:26:00,680 LEADS TO RAPID PROGRESSION DOWN 1667 01:26:00,680 --> 01:26:03,280 THE MALIGNANCY PATHWAY AND 1668 01:26:03,280 --> 01:26:05,240 CLINICALLY, CAN WE USE A DRUG TO 1669 01:26:05,240 --> 01:26:07,280 REVERSE THIS EFFECT AND PUSH 1670 01:26:07,280 --> 01:26:09,200 THINGS BACK TOWARDS WHERE THINGS 1671 01:26:09,200 --> 01:26:11,480 ARE A LITTLE BIT LESS LIKELY TO 1672 01:26:11,480 --> 01:26:12,840 TRANSFORM INTO MALIGNANCY. 1673 01:26:12,840 --> 01:26:16,080 THAT'S WHAT I THINK TUMOR 1674 01:26:16,080 --> 01:26:19,120 HETEROGENEITY IS TEACHING US AND 1675 01:26:19,120 --> 01:26:24,520 THIS RESOLUTION OF SINGLE CELL 1676 01:26:24,520 --> 01:26:27,480 ALLOWS US TO COME UP WITH IDEAS. 1677 01:26:27,480 --> 01:26:32,160 WE HAVE TAKE HOME MESSAGES AND 1678 01:26:32,160 --> 01:26:34,080 NF 1s ARE GREAT CLINICAL 1679 01:26:34,080 --> 01:26:36,960 TEACHERS AND THEIR CLINICAL 1680 01:26:36,960 --> 01:26:37,240 TEACHERS. 1681 01:26:37,240 --> 01:26:40,720 YOU'VE SEEN THAT IN BRIGITTE'S 1682 01:26:40,720 --> 01:26:42,400 PRESENTATION AND HOPEFULLY MINE 1683 01:26:42,400 --> 01:26:44,920 AND THE CLINIC CENTER IS A GREAT 1684 01:26:44,920 --> 01:26:48,800 PLACE TO STUDY THE DISEASES AND 1685 01:26:48,800 --> 01:26:51,240 NF 1 IS A GREAT TEACHER BECAUSE 1686 01:26:51,240 --> 01:26:56,080 THE CLINICAL PROGRESSION 1687 01:26:56,080 --> 01:26:57,400 MIRRORING THE PROGRESSION AND 1688 01:26:57,400 --> 01:26:59,840 THINK WE'RE MAKING PROGRESS IN 1689 01:26:59,840 --> 01:27:02,360 TREATING THE BENIGN TUMORS BUT 1690 01:27:02,360 --> 01:27:04,920 ONCE IT TRANSFERS TO MALIGNANCY 1691 01:27:04,920 --> 01:27:09,880 THE PROGNOSIS IS POOR. 1692 01:27:09,880 --> 01:27:11,400 THE TECHNOLOGY IS MOVING RAPIDLY 1693 01:27:11,400 --> 01:27:13,480 ENOUGH THAT WE SHOULD HAVE THESE 1694 01:27:13,480 --> 01:27:15,040 THINGS IN THE CLINICS SOON. 1695 01:27:15,040 --> 01:27:16,880 AND FINALLY PATIENT ENGAGEMENT 1696 01:27:16,880 --> 01:27:19,120 AND COLLABORATION ARE CRITICAL 1697 01:27:19,120 --> 01:27:22,640 TO MAKING ADVANCES HERE AND OUR 1698 01:27:22,640 --> 01:27:23,800 PATIENTS ARE THE ONES THAT 1699 01:27:23,800 --> 01:27:28,880 TAUGHT US ORIGINALLY AND THEY'RE 1700 01:27:28,880 --> 01:27:30,760 TEACHING US AGAIN AND AGAIN HOW 1701 01:27:30,760 --> 01:27:32,320 TO DO THIS BETTER AND THIS IS 1702 01:27:32,320 --> 01:27:36,240 WHAT WE RAN FOR SOME PATIENTS 1703 01:27:36,240 --> 01:27:38,280 WHERE WE TAKE THEM OUT TO HAVE A 1704 01:27:38,280 --> 01:27:43,360 SUMMER CAMP AND IT'S GREAT FUN 1705 01:27:43,360 --> 01:27:48,800 FOR EVERYBODY AND THIS SAY HUGE 1706 01:27:48,800 --> 01:27:50,200 TEAM OF PEOPLE THAT HAVE DONE 1707 01:27:50,200 --> 01:27:51,840 THE WORK AND WE'RE HERE TO 1708 01:27:51,840 --> 01:27:52,920 DELIVER THE MESSAGE. 1709 01:27:52,920 --> 01:27:54,720 THERE'S LOTS OF PEOPLE BEHIND 1710 01:27:54,720 --> 01:27:56,480 THE SCENES WHO HAVE BEEN GREAT 1711 01:27:56,480 --> 01:27:58,520 COLLABORATORS TO US OVER THE 1712 01:27:58,520 --> 01:27:58,960 YEARS. 1713 01:27:58,960 --> 01:28:00,920 I GUESS I'LL STOP THERE AND WE 1714 01:28:00,920 --> 01:28:16,120 CAN OPEN THE DISCUSSION. 1715 01:28:16,120 --> 01:28:16,840 >> OKAY. 1716 01:28:16,840 --> 01:28:18,000 THANK YOU BOTH. 1717 01:28:18,000 --> 01:28:19,720 EXCITING IS TOO MINIMUM OF A 1718 01:28:19,720 --> 01:28:21,560 WORD TO ADD TO THE ENORMOUS WORK 1719 01:28:21,560 --> 01:28:24,480 PRESENTATIONS AND THE DIMENSIONS 1720 01:28:24,480 --> 01:28:30,560 OF WHAT THE FUTURE MAY HOLD FOR 1721 01:28:30,560 --> 01:28:31,600 THIS. 1722 01:28:31,600 --> 01:28:37,520 IT STRUCK ME THAT THIS IS AN 1723 01:28:37,520 --> 01:28:38,520 INTERESTING EXAMPLE. 1724 01:28:38,520 --> 01:28:40,880 CLINICAL OBSERVATIONS OF PEOPLE 1725 01:28:40,880 --> 01:28:43,120 TAKING DRUGS MUCH LATER LED TO 1726 01:28:43,120 --> 01:28:43,720 THE MECHANISM OF HOW A DRUG 1727 01:28:43,720 --> 01:28:51,480 ACTS. 1728 01:28:51,480 --> 01:28:54,680 AND THIS IS MODERN SCIENCE 1729 01:28:54,680 --> 01:28:56,880 SOMEWHAT IN REVERSE WHERE A 1730 01:28:56,880 --> 01:29:01,520 CLINICAL TRIAL BASED UPON AN 1731 01:29:01,520 --> 01:29:03,760 EXPERIMENT 1732 01:29:03,760 --> 01:29:05,480 EXPERIMENTAL MECHANISM LEADS TO 1733 01:29:05,480 --> 01:29:09,680 A WHOLE EXPANSION OF SCIENCE AS 1734 01:29:09,680 --> 01:29:13,160 APPLIED AND THE DRIVING FORCE IS 1735 01:29:13,160 --> 01:29:16,480 THE CLINICAL TRIAL. 1736 01:29:16,480 --> 01:29:19,080 I SUSPECT IF THAT HAD NOT 1737 01:29:19,080 --> 01:29:20,040 HAPPENED YOU'D BE DOING 1738 01:29:20,040 --> 01:29:24,920 SOMETHING ELSE OR NOT HAVE THE 1739 01:29:24,920 --> 01:29:26,080 SAME ENTHUSIASM WHICH SEEMS TO 1740 01:29:26,080 --> 01:29:26,640 BE JUSTIFIABLE. 1741 01:29:26,640 --> 01:29:34,080 WE HAVE A BUNCH OF QUESTIONS. 1742 01:29:34,080 --> 01:29:36,000 EACH OF YOU DECIDE HOW YOU WANT 1743 01:29:36,000 --> 01:29:36,880 TO DEAL WITH IT. 1744 01:29:36,880 --> 01:29:45,280 WHY DO YOU THINK SOME PATIENTS 1745 01:29:45,280 --> 01:29:47,720 WITH NF 1 MUTATIONS DON'T 1746 01:29:47,720 --> 01:29:49,400 RESPOND TO THE MEK INHIBITER AND 1747 01:29:49,400 --> 01:29:55,800 ARE THEY THE ONES THAT HAVE THE 1748 01:29:55,800 --> 01:29:57,240 MUTATION OR ARE THERE OTHER 1749 01:29:57,240 --> 01:29:57,480 MUTATIONS? 1750 01:29:57,480 --> 01:30:02,680 WHAT DO YOU THINK ABOUT THAT S&P 1751 01:30:02,680 --> 01:30:03,000 -- THAT? 1752 01:30:03,000 --> 01:30:04,680 >> THAT'S A GREAT QUESTION AND 1753 01:30:04,680 --> 01:30:09,680 EXACTLY RIGHT. 1754 01:30:09,680 --> 01:30:16,760 I WOULD SAY THE PLEXIFORM 1755 01:30:16,760 --> 01:30:18,880 NEUROFIBROMAS ALMOST ALL 1756 01:30:18,880 --> 01:30:19,160 RESPONSE. 1757 01:30:19,160 --> 01:30:22,800 THE MAGNITUDE MAY VARY BUT WE'VE 1758 01:30:22,800 --> 01:30:25,000 SEEN SHRINKAGE IN ALMOST ALL OF 1759 01:30:25,000 --> 01:30:26,400 THEM. 1760 01:30:26,400 --> 01:30:36,000 IF A TUMOR LOST THE CDNK2A THAT 1761 01:30:36,000 --> 01:30:40,680 QUALITIES AS AN ATYPICAL FIBROMA 1762 01:30:40,680 --> 01:30:42,480 AND MAY CONTINUE TO GROW. 1763 01:30:42,480 --> 01:30:44,880 I THINK THAT'S OUR CURRENT 1764 01:30:44,880 --> 01:31:07,160 THINKING. 1765 01:31:07,160 --> 01:31:07,400 1766 01:31:07,400 --> 01:31:09,720 >> HOW MUCH GETS IN A TUMOR 1767 01:31:09,720 --> 01:31:12,600 DEPENDS ON HOW DENSE IT IS. 1768 01:31:12,600 --> 01:31:17,680 IT'S MULTI-FACTORIAL BUT I THINK 1769 01:31:17,680 --> 01:31:24,480 IF IT'S GOTTEN THE CDNK2A LESION 1770 01:31:24,480 --> 01:31:26,160 AND THESE WE WANT TO COME UP 1771 01:31:26,160 --> 01:31:39,920 WITH A NEW THERAPY. 1772 01:31:39,920 --> 01:31:42,080 >> THERE'S A CERTAIN SPECIFICITY 1773 01:31:42,080 --> 01:31:43,400 FOR THE TUMOR TO PARTICIPATE IN 1774 01:31:43,400 --> 01:31:50,000 CELL GROWTH ALL OVER THE BODY. 1775 01:31:50,000 --> 01:31:51,520 AND MAYBE SOME TOXICITY IS 1776 01:31:51,520 --> 01:31:53,280 RELATED TO IT BUT SEEMS 1777 01:31:53,280 --> 01:31:56,880 EXTRAORDINARY THE AFFECT ON THE 1778 01:31:56,880 --> 01:32:00,280 TUMOR WOULD DOMINANT OVER THE 1779 01:32:00,280 --> 01:32:00,640 TOXICITY. 1780 01:32:00,640 --> 01:32:07,120 ARE THERE EFFORTS TO TRY AND 1781 01:32:07,120 --> 01:32:12,880 TARGET THE MEK INHIBITOR TO THE 1782 01:32:12,880 --> 01:32:14,760 TUMOR EVEN NANO SYSTEMS? 1783 01:32:14,760 --> 01:32:21,560 WHAT'S THE THINKING ABOUT THAT? 1784 01:32:21,560 --> 01:32:23,640 >> IT'S FUNNY YOU BRING THAT UP. 1785 01:32:23,640 --> 01:32:24,960 IT'S AN INCREDIBLE IDEA AND I 1786 01:32:24,960 --> 01:32:28,840 THINK WE HAD A MEETING A COUPLE 1787 01:32:28,840 --> 01:32:30,240 WEEKS BACK WHERE IT WAS WHERE, 1788 01:32:30,240 --> 01:32:36,840 WE SHOULD WORK ON THIS. 1789 01:32:36,840 --> 01:32:38,240 I THINK THE DETAILED 1790 01:32:38,240 --> 01:32:38,840 UNDERSTANDING OF THE 1791 01:32:38,840 --> 01:32:40,360 MICROENVIRONMENTS AND THE 1792 01:32:40,360 --> 01:32:43,160 TARGETS THERE WILL HELP DEFINE 1793 01:32:43,160 --> 01:32:44,840 THE RIGHT STRATEGY TO DELIVER A 1794 01:32:44,840 --> 01:32:48,480 DRUG IN A BETTER WAY. 1795 01:32:48,480 --> 01:32:51,440 THAT'S ANOTHER BYPRODUCT OF 1796 01:32:51,440 --> 01:32:52,600 HAVING THE DETAILED 1797 01:32:52,600 --> 01:32:54,120 UNDERSTANDING OF THE 1798 01:32:54,120 --> 01:32:54,440 ENVIRONMENT. 1799 01:32:54,440 --> 01:32:56,920 YOU CAN IMAGINE IT BECOMES AN 1800 01:32:56,920 --> 01:32:57,680 ENGINEERING PROBLEM. 1801 01:32:57,680 --> 01:33:03,640 HOW DO YOU GET MORE DRUG TO THAT 1802 01:33:03,640 --> 01:33:03,840 REGION? 1803 01:33:03,840 --> 01:33:05,120 THAT'S WHAT I LOVE YOU 1804 01:33:05,120 --> 01:33:07,840 UNDERSTAND THE MECHANISM AND 1805 01:33:07,840 --> 01:33:09,600 THAN CAN ENGINEER YOU'RE WAY TO 1806 01:33:09,600 --> 01:33:10,440 FIXING IT. 1807 01:33:10,440 --> 01:33:15,280 >> AN INTERESTING TALK TWO WEEKS 1808 01:33:15,280 --> 01:33:18,800 AGO THAT THE BIO ENGINEERING 1809 01:33:18,800 --> 01:33:20,600 DEPARTMENT AT M.I.T. GAVE 1810 01:33:20,600 --> 01:33:25,200 DEALING IN PART WITH SUCH ISSUES 1811 01:33:25,200 --> 01:33:30,880 AND STUDIES THEY'VE DONE USING 1812 01:33:30,880 --> 01:33:34,280 NANO 2 DELIVERIES AND THERE'S A 1813 01:33:34,280 --> 01:33:39,560 QUESTION ABOUT ENVIRONMENTAL 1814 01:33:39,560 --> 01:33:41,680 FACTORS AND WHETHER THEY 1815 01:33:41,680 --> 01:33:43,240 INFLUENCE THE PROGRESSION OF THE 1816 01:33:43,240 --> 01:33:48,000 TUMOR OR RESPONSIVENESS TO 1817 01:33:48,000 --> 01:33:50,560 THERAPY SPECIFICALLY THE SUN WAS 1818 01:33:50,560 --> 01:33:50,840 MENTIONED. 1819 01:33:50,840 --> 01:33:53,080 IS THERE ENVIRONMENTAL 1820 01:33:53,080 --> 01:33:55,280 INFORMATION THAT GIVES SOME CLUE 1821 01:33:55,280 --> 01:34:00,600 ABOUT THAT? 1822 01:34:00,600 --> 01:34:04,880 >> I'M NOT AWARE OF GOOD CLUES. 1823 01:34:04,880 --> 01:34:06,600 THERE'S BEEN THOUGHTS ON VITAMIN 1824 01:34:06,600 --> 01:34:10,000 D AND SUN EXPOSURE AND MANY, FOR 1825 01:34:10,000 --> 01:34:14,520 EXAMPLE OF THE CUTANEOUS TUMORS 1826 01:34:14,520 --> 01:34:18,280 ARE ON THE TRUNK BUT THE DENSITY 1827 01:34:18,280 --> 01:34:20,160 OF THE TUMORS AND THE THOUGHT 1828 01:34:20,160 --> 01:34:23,920 WAS COULD IT BE RELATED TO LACK 1829 01:34:23,920 --> 01:34:29,000 OF SUN EXPOSURE BUT I DON'T 1830 01:34:29,000 --> 01:34:38,160 THINK IT'S A STRONG LINK. 1831 01:34:38,160 --> 01:34:40,360 WE TRY TO AVOID RADIATION 1832 01:34:40,360 --> 01:34:43,560 BECAUSE WE THINK RADIATION TO A 1833 01:34:43,560 --> 01:34:45,000 CELL ALREADY PREDISPOSED TO 1834 01:34:45,000 --> 01:34:46,680 DEVELOP TUMORS MAYBE AT A 1835 01:34:46,680 --> 01:34:48,840 GREATER RISK FOR MALIGNANT 1836 01:34:48,840 --> 01:34:51,120 TRANSFORMATION. 1837 01:34:51,120 --> 01:34:53,400 WE VERY MUCH TRIED TO AVOID 1838 01:34:53,400 --> 01:34:56,320 RADIATION IN NF 1 PATIENTS 1839 01:34:56,320 --> 01:35:00,920 UNLESS CLINICALLY NEEDED AND 1840 01:35:00,920 --> 01:35:03,960 RADIATION CAN EXACERBATE 1841 01:35:03,960 --> 01:35:06,040 VASCULOPATHY BUT OUTSIDE OF THAT 1842 01:35:06,040 --> 01:35:07,120 HORMONAL FACTORS HAVE BEEN 1843 01:35:07,120 --> 01:35:13,560 DISCUSSED. 1844 01:35:13,560 --> 01:35:16,080 FOR EXAMPLE WHEN WOMEN ARE 1845 01:35:16,080 --> 01:35:19,200 PREGNANT SOME DESCRIBE THOUSANDS 1846 01:35:19,200 --> 01:35:22,480 OF SUB CUTANEOUS TUMORS ERUPT 1847 01:35:22,480 --> 01:35:32,960 AND MANY TELL ME THEY WERE 1848 01:35:32,960 --> 01:35:36,480 DIAGNOS 1849 01:35:36,480 --> 01:35:36,920 DIAGNOSED. 1850 01:35:36,920 --> 01:35:42,040 >> THERE'S A QUESTION WHETHER 1851 01:35:42,040 --> 01:35:47,160 THERE ARE I GUESS GEOGRAPHIC HOT 1852 01:35:47,160 --> 01:35:51,080 SPOTS AND THERE'S MANY 1853 01:35:51,080 --> 01:35:53,360 RECESSIVELY INHERITED NF 1s AND 1854 01:35:53,360 --> 01:35:55,960 GRANTED THIS IS A MORE DOMINANT 1855 01:35:55,960 --> 01:35:59,400 TRANSMISSION BUT ARE THERE HOT 1856 01:35:59,400 --> 01:36:00,080 SPOTS GEOGRAPHICALLY? 1857 01:36:00,080 --> 01:36:03,400 >> NOT THAT I'M AWARE OF. 1858 01:36:03,400 --> 01:36:06,280 I'M PRETTY SURE IT'S NOT BEEN 1859 01:36:06,280 --> 01:36:24,320 DESCRIBED FOR NF 1. 1860 01:36:24,320 --> 01:36:25,320 >> AN INTERESTING THING ABOUT 1861 01:36:25,320 --> 01:36:27,840 THE GENE IS IT'S HUGE. 1862 01:36:27,840 --> 01:36:29,720 JUST THE SIZE IN SOME PERCENTAGE 1863 01:36:29,720 --> 01:36:32,120 OF THE POPULATION YOU'LL GET AN 1864 01:36:32,120 --> 01:36:37,920 ERROR THAT OCCURS IN THAT 1865 01:36:37,920 --> 01:36:38,400 FASHION. 1866 01:36:38,400 --> 01:36:39,920 I DON'T KNOW IF ANY GEOGRAPHIC 1867 01:36:39,920 --> 01:36:41,600 REGION BUT INTERESTING TO THINK 1868 01:36:41,600 --> 01:36:42,840 IT'S A HUGE GENE WITH A LOT OF 1869 01:36:42,840 --> 01:36:44,080 OPPORTUNITIES FOR THINGS TO GO 1870 01:36:44,080 --> 01:36:54,840 WRONG IN MY THINKING. 1871 01:36:54,840 --> 01:36:58,560 >> YOU MENTIONED THE GTP 1872 01:36:58,560 --> 01:36:59,720 ACTIVATING PROTEIN. 1873 01:36:59,720 --> 01:37:15,080 IS IT CIRCULATING IN BLOOD? 1874 01:37:15,080 --> 01:37:17,240 >> I DON'T KNOW THE ANSWER TO 1875 01:37:17,240 --> 01:37:17,520 THAT. 1876 01:37:17,520 --> 01:37:18,480 >> I HAVE TO PASS. 1877 01:37:18,480 --> 01:37:18,840 I DON'T KNOW. 1878 01:37:18,840 --> 01:37:31,800 THAT'S A GREAT QUESTION. 1879 01:37:31,800 --> 01:37:33,680 >> IT'S AN INTRACELLULAR PROTEIN 1880 01:37:33,680 --> 01:37:35,240 BUT I DON'T KNOW WE'VE LOOKED IN 1881 01:37:35,240 --> 01:37:48,760 THE SERUM SAMPLES. 1882 01:37:48,760 --> 01:37:52,280 NEUROFIBROMIN IS SYNTHESISED BY 1883 01:37:52,280 --> 01:37:52,840 WHAT CELLS? 1884 01:37:52,840 --> 01:37:56,840 >> IT'S NOT RESTRICTED TO 1885 01:37:56,840 --> 01:37:59,200 PARTICULAR LINEAGES. 1886 01:37:59,200 --> 01:38:06,040 >> WOULD IT BE IN HEPATOCYTES 1887 01:38:06,040 --> 01:38:08,200 FOR EXAMPLE? 1888 01:38:08,200 --> 01:38:12,840 >> YEAH, IT'S IMPORTANT IN MANY 1889 01:38:12,840 --> 01:38:25,880 CELLS IN DIFFERENT LINEAGES. 1890 01:38:25,880 --> 01:38:27,840 >> THERE'S COMMUNICATION BETWEEN 1891 01:38:27,840 --> 01:38:31,560 THE MEK AND RAS PATHWAY. 1892 01:38:31,560 --> 01:38:35,120 IS THEY ARE ROLE FOR PI3 KINASE 1893 01:38:35,120 --> 01:38:40,880 IN THESE RESPONSES? 1894 01:38:40,880 --> 01:38:45,400 AND THERE ARE NOW VARIOUS KINASE 1895 01:38:45,400 --> 01:38:48,880 INHIBITERS. 1896 01:38:48,880 --> 01:38:56,040 IS THAT WORTH INVESTIGATING? 1897 01:38:56,040 --> 01:38:59,640 >> I CAN SAY THAT THAT PATHWAY 1898 01:38:59,640 --> 01:39:00,840 IS ACTIVATED PERHAPS IN A 1899 01:39:00,840 --> 01:39:03,840 DIFFERENT WAY AND THAT WAS THE 1900 01:39:03,840 --> 01:39:05,080 RATIONALE BETWEEN THE MPNST 1901 01:39:05,080 --> 01:39:12,840 TRIAL WHERE WE TRIED TO ADD A 1902 01:39:12,840 --> 01:39:15,360 MEK INHIBITER AND WHEN YOU START 1903 01:39:15,360 --> 01:39:18,560 TO INHIBIT BOTH THE TOXICITY 1904 01:39:18,560 --> 01:39:20,120 GOES HIGH. 1905 01:39:20,120 --> 01:39:23,480 YOU CAN IMAGINE IN A BENIGN 1906 01:39:23,480 --> 01:39:25,680 CONDITION OF PLEXIFORM 1907 01:39:25,680 --> 01:39:26,680 NEUROFIBROMAS YOU WOULDN'T 1908 01:39:26,680 --> 01:39:27,840 TOLERATE MUCH TOXICITY AT ALL 1909 01:39:27,840 --> 01:39:31,680 AND THAT'S A BENEFIT OF THE 1910 01:39:31,680 --> 01:39:32,880 SELUMETINIB IS THE TOXICITY 1911 01:39:32,880 --> 01:39:43,120 PROFILE IS FAIRLY WELL HANDLED. 1912 01:39:43,120 --> 01:39:47,440 >> THEY LOOK AT THE KINASE 1913 01:39:47,440 --> 01:39:49,240 INHIBITERS AS WELL AND WOULD BE 1914 01:39:49,240 --> 01:39:50,680 INTERESTING TO EXPLORE IN 1915 01:39:50,680 --> 01:39:54,280 COMBINATION WITH THE MEK 1916 01:39:54,280 --> 01:39:56,880 INHIBITOR BUT JACK HAS A GREAT 1917 01:39:56,880 --> 01:40:00,920 POINT IN THE PATIENTS WHO HAVE 1918 01:40:00,920 --> 01:40:06,960 BENIGN TUMORS PARTICULARLY IN 1919 01:40:06,960 --> 01:40:12,880 YOUNG KIDS THEY'RE NOT AS LIKELY 1920 01:40:12,880 --> 01:40:16,840 TO TOLERATE AS MUCH TOXICITY AND 1921 01:40:16,840 --> 01:40:22,840 IT'S TOO MUCH AND PATIENTS ARE 1922 01:40:22,840 --> 01:40:26,840 MORE LIKELY TO PUT OUT THE 1923 01:40:26,840 --> 01:40:28,920 TOXICITIES THEY SEE IN HOPES OF 1924 01:40:28,920 --> 01:40:30,120 BETTER RESPONSE AND SOMETHING TO 1925 01:40:30,120 --> 01:40:35,440 CONSIDER AS WE DEVELOP MEDICINES 1926 01:40:35,440 --> 01:40:37,680 FOR THE TUMORS. 1927 01:40:37,680 --> 01:40:39,880 >> WE HAVE A FEW WHAT I CALL 1928 01:40:39,880 --> 01:40:50,880 GENERAL CLINICAL RELATED THINGS. 1929 01:40:50,880 --> 01:40:56,880 DOES THE AMERICAN ACADEMY OF 1930 01:40:56,880 --> 01:41:01,120 PEDIATRICS REALLY REQUIRE 1931 01:41:01,120 --> 01:41:05,200 PEDIATRICIANS KNOW SOMETHING 1932 01:41:05,200 --> 01:41:07,040 ABOUT NF 1 AND ARE YOU CONFIDENT 1933 01:41:07,040 --> 01:41:08,560 MOST PEDIATRICIANS KNOW ABOUT IT 1934 01:41:08,560 --> 01:41:12,880 AND IF NOT HOW DO YOU 1935 01:41:12,880 --> 01:41:15,480 DISSEMINATE THE INFORMATION? 1936 01:41:15,480 --> 01:41:16,840 >> HAVING BEEN THROUGH PEDIATRIC 1937 01:41:16,840 --> 01:41:18,280 RESIDENCY THIS IS SOMETHING YOU 1938 01:41:18,280 --> 01:41:20,240 DO LOOK FOR AS A GENERAL 1939 01:41:20,240 --> 01:41:21,920 PEDIATRICIAN AND THE SKIN 1940 01:41:21,920 --> 01:41:26,800 FINDINGS ARE SO STEREOTYPICAL IF 1941 01:41:26,800 --> 01:41:28,920 YOU SEE MULTIPLE CAFE AU LAIT 1942 01:41:28,920 --> 01:41:31,680 SPOTS OR THE UNIQUE CLINICAL 1943 01:41:31,680 --> 01:41:35,880 FINDINGS, IT'S ENGRAINED IN THE 1944 01:41:35,880 --> 01:41:55,120 PEDIATRICIANS HEAD THIS IS NF 1. 1945 01:41:55,120 --> 01:41:57,600 >> AND IF THE FDA APPROVES THE 1946 01:41:57,600 --> 01:42:00,920 USE OF THE INHIBITOR, QUESTION 1947 01:42:00,920 --> 01:42:06,680 PRACTICAL, IS ITS COVERED BY 1948 01:42:06,680 --> 01:42:08,880 INSURANCE AND HOW MUCH DOES IT 1949 01:42:08,880 --> 01:42:10,240 COST? 1950 01:42:10,240 --> 01:42:11,920 >> IT'S INTERESTING. 1951 01:42:11,920 --> 01:42:15,320 WE TALK WITH ASTRAZENECA THEY 1952 01:42:15,320 --> 01:42:17,280 DEVELOP THE SELUMETINIB I STILL 1953 01:42:17,280 --> 01:42:19,800 CAN'T GIVE A PRECISE ANSWER BUT 1954 01:42:19,800 --> 01:42:21,840 I DO THINK THERE'S COVERAGE BY 1955 01:42:21,840 --> 01:42:24,720 ENSURANCE AND THERE'S A NUMBER 1956 01:42:24,720 --> 01:42:29,040 OF MECHANISMS FOR PATIENTS WHO 1957 01:42:29,040 --> 01:42:31,120 DON'T HAVE THE MEANS. 1958 01:42:31,120 --> 01:42:36,080 AND GET ACCESS TO THE MEK 1959 01:42:36,080 --> 01:42:36,680 INHIBIT 1960 01:42:36,680 --> 01:42:36,960 INHIBITOR. 1961 01:42:36,960 --> 01:42:38,240 I WOULD EXPECT IT'S NOT 1962 01:42:38,240 --> 01:42:40,920 INEXPENSIVE BECAUSE MOST THE 1963 01:42:40,920 --> 01:42:44,240 DRUGS IN THIS AREA WITH THE 1964 01:42:44,240 --> 01:42:46,840 KINASE INHIBITOR DEVELOPED ARE 1965 01:42:46,840 --> 01:42:48,200 QUITE EXPENSIVE. 1966 01:42:48,200 --> 01:42:51,360 THE INTERESTING ASPECT IN NF 1 1967 01:42:51,360 --> 01:42:52,600 IS WE HAVE PATIENTS THAT HAVE 1968 01:42:52,600 --> 01:42:58,000 BEEN ON IT FOR YEARS AND IT'S AT 1969 01:42:58,000 --> 01:43:05,480 THE CHRONIC MEDICINE BUT A 1970 01:43:05,480 --> 01:43:08,120 NUMBER OF THEM HELP PATIENTS GET 1971 01:43:08,120 --> 01:43:08,360 ACCESS. 1972 01:43:08,360 --> 01:43:09,080 SORRY I CAN'T ANSWER THE PRECISE 1973 01:43:09,080 --> 01:43:14,240 QUESTION. 1974 01:43:14,240 --> 01:43:14,920 >> DO PATIENTS RELAPSE ON THE 1975 01:43:14,920 --> 01:43:19,600 DRUG 1976 01:43:19,600 --> 01:43:22,720 >> PATIENTS WHO STOP TAKING THE 1977 01:43:22,720 --> 01:43:24,680 MEDICINE FOR EXAMPLE ADOLESCENTS 1978 01:43:24,680 --> 01:43:30,520 MAY STOP TAKING IT THE TUMORS 1979 01:43:30,520 --> 01:43:34,560 WILL LIKELY GROW WE HAVE FEW 1980 01:43:34,560 --> 01:43:36,280 PATIENTS WITH BENIGN TUMORS WHO 1981 01:43:36,280 --> 01:43:37,160 DEVELOP PROGRESSION AND 1982 01:43:37,160 --> 01:43:37,440 TREATMENT. 1983 01:43:37,440 --> 01:43:40,840 THERE'S A FEW. 1984 01:43:40,840 --> 01:43:42,560 WE CERTAINLY HAVE SEEN RELAPSE 1985 01:43:42,560 --> 01:43:45,840 OF PROGRESSION IN PATIENTS WHO 1986 01:43:45,840 --> 01:43:48,320 UNDER GO GOES REDUCTION FOR 1987 01:43:48,320 --> 01:43:48,840 TOXICITY. 1988 01:43:48,840 --> 01:43:49,960 THE RELATIVELY SMALL NUMBER OF 1989 01:43:49,960 --> 01:43:52,160 PATIENTS WITH A DOSE REDUCTION 1990 01:43:52,160 --> 01:43:53,480 SOME OF THEM WILL HAVE GROWTH OF 1991 01:43:53,480 --> 01:43:55,080 TUMORS BECAUSE THEY DON'T SEEM 1992 01:43:55,080 --> 01:44:00,720 TO GET THE ADEQUATE DOSE. 1993 01:44:00,720 --> 01:44:03,640 WE HAVE TO HOLD FOR TOXICITY OF 1994 01:44:03,640 --> 01:44:08,920 SURGERY OR FOR SOME REASON THE 1995 01:44:08,920 --> 01:44:12,240 TUMOR WILL REGROW AND IT WILL 1996 01:44:12,240 --> 01:44:14,680 TYPICALLY RESPOND TO THE MEK 1997 01:44:14,680 --> 01:44:14,920 INHIBITOR. 1998 01:44:14,920 --> 01:44:16,560 THOSE ARE INTERESTING 1999 01:44:16,560 --> 01:44:16,880 OBSERVATIONS. 2000 01:44:16,880 --> 01:44:20,080 >> THERE'S A LITTLE EVIDENCE FOR 2001 01:44:20,080 --> 01:44:24,960 THE DEVELOPMENT OF REAL 2002 01:44:24,960 --> 01:44:25,280 RESISTANCE. 2003 01:44:25,280 --> 01:44:35,000 >> THAT IS CORRECT. 2004 01:44:35,000 --> 01:44:40,920 WE HAVE RESPONSES TO SEE THE 2005 01:44:40,920 --> 01:44:50,320 RESISTANCE AFTERWARDS. 2006 01:44:50,320 --> 01:44:52,760 >> DO YOU PATIENTS WITH NF 1 2007 01:44:52,760 --> 01:44:57,920 BECOME PREGNANT OR DO THEY 2008 01:44:57,920 --> 01:45:00,120 USUALLY CHOOSE ADOPTION. 2009 01:45:00,120 --> 01:45:00,920 >> YOU CAN ABSOLUTELY HAVE 2010 01:45:00,920 --> 01:45:10,240 CHILDREN. 2011 01:45:10,240 --> 01:45:12,800 WE HAVE A NUMBER OF PATIENTS 2012 01:45:12,800 --> 01:45:19,400 THAT HAVE OFFSPRING WITH NF 1 2013 01:45:19,400 --> 01:45:20,200 AND WITHOUT. 2014 01:45:20,200 --> 01:45:28,880 YES. 2015 01:45:28,880 --> 01:45:31,840 >> ARE THEY ALL BY IN VITRO 2016 01:45:31,840 --> 01:45:32,280 FERTILIZATION. 2017 01:45:32,280 --> 01:45:35,680 >> YOU HAVE HALF THE PATIENTS WE 2018 01:45:35,680 --> 01:45:38,200 HAVE A FAMILY HISTORY OF NF 1 2019 01:45:38,200 --> 01:45:40,320 WHERE THE MOM OR DAD HAD IT AND 2020 01:45:40,320 --> 01:45:41,760 THEY KNOW ABOUT IT OR DON'T KNOW 2021 01:45:41,760 --> 01:45:43,160 ABOUT IT. 2022 01:45:43,160 --> 01:45:45,240 THE MAJORITY WOULD KNOW THEY 2023 01:45:45,240 --> 01:45:48,920 HAVE NF 1. 2024 01:45:48,920 --> 01:45:50,920 AND THE OTHERS HAVE SPONTANEOUS 2025 01:45:50,920 --> 01:45:52,880 MUTATIONS THAT OCCUR. 2026 01:45:52,880 --> 01:45:58,640 >> SO IT'S NOT THAT THEY HAVE 2027 01:45:58,640 --> 01:46:00,960 PRENATAL TESTING LIKE ASSOCIATED 2028 01:46:00,960 --> 01:46:03,640 WITH IN VITRO FERTILIZATION. 2029 01:46:03,640 --> 01:46:06,760 >> THE ABILITY TO DO PRENATAL 2030 01:46:06,760 --> 01:46:12,760 TESTING FOR THE PRESENCE OF NF 2031 01:46:12,760 --> 01:46:12,880 1. 2032 01:46:12,880 --> 01:46:16,880 FOR EXAMPLE, IF YOU HAVE A 2033 01:46:16,880 --> 01:46:18,960 FAMILY HISTORY AND YOU WANT TO 2034 01:46:18,960 --> 01:46:20,880 BECOME PREGNANT AND YOU HAVE NF 2035 01:46:20,880 --> 01:46:26,080 1 OR YOUR PARTNER HAS NF 1 MANY 2036 01:46:26,080 --> 01:46:32,960 LEAD TO THE PHENOTYPE 2037 01:46:32,960 --> 01:46:33,280 CORRELATIONS. 2038 01:46:33,280 --> 01:46:37,160 WE MAY HAVE THE MOM VERY 2039 01:46:37,160 --> 01:46:39,200 MULTI-AFFECTED BUT DOESN'T 2040 01:46:39,200 --> 01:46:48,920 PREDICT THE CHILD WILL BE MILDLY 2041 01:46:48,920 --> 01:46:49,960 AFFECTED. 2042 01:46:49,960 --> 01:46:55,760 THERE'S SO LITTLE PREDICTABILITY 2043 01:46:55,760 --> 01:46:56,920 OF CORRELATIONS. 2044 01:46:56,920 --> 01:46:59,320 >> 2045 01:46:59,320 --> 01:47:09,000 >> AMONGST THE MANY OTHER OMAS 2046 01:47:09,000 --> 01:47:11,680 AND ALL OF THAT, ARE THEY ALL 2047 01:47:11,680 --> 01:47:17,480 RELATED ONE WAY OR ANOTHER TO NF 2048 01:47:17,480 --> 01:47:19,840 1 OR NF 2? 2049 01:47:19,840 --> 01:47:24,840 >> I WOULD SAY NOT ALL OF THEM. 2050 01:47:24,840 --> 01:47:28,880 AN NF 1 GLIOMAS WE SEE MORE 2051 01:47:28,880 --> 01:47:32,560 FREQUENTLY AND IN NF 2 2052 01:47:32,560 --> 01:47:35,480 CHROMOSOME 22 A COMPLETELY 2053 01:47:35,480 --> 01:47:40,880 DIFFERENT GENETIC BASIS WE SEE 2054 01:47:40,880 --> 01:47:46,920 BILATERAL VESTIBULAR SCHWANNOMAS 2055 01:47:46,920 --> 01:48:03,520 AND IN SCHWANNOMATOSIS AND SEE 2056 01:48:03,520 --> 01:48:04,840 OTHERS WITHOUT A GENETIC BASE 2057 01:48:04,840 --> 01:48:06,040 FOR IT. 2058 01:48:06,040 --> 01:48:09,240 >> WHEN YOU SAY SPORADIC, IS 2059 01:48:09,240 --> 01:48:16,280 THAT ACTUALLY BEEN TESTS? 2060 01:48:16,280 --> 01:48:20,840 COULD THERE BE HETEROZYGOTE FORM 2061 01:48:20,840 --> 01:48:23,960 OF MUTATION WITH SUSCEPTIBILITY? 2062 01:48:23,960 --> 01:48:26,160 COULD THEY ALL BE RELATED? 2063 01:48:26,160 --> 01:48:28,880 >> I'M PRETTY SURE THEY'VE BEEN 2064 01:48:28,880 --> 01:48:31,920 EXAMINED AN IT'S TRUE SPORADIC 2065 01:48:31,920 --> 01:48:40,920 AT LEAST NF 1 AND NF 2 AND 2066 01:48:40,920 --> 01:48:50,080 SCHWANNOOMA TOSE IS HAS BEEN 2067 01:48:50,080 --> 01:48:54,840 RULED OUT 2068 01:48:54,840 --> 01:48:56,480 >> THERE'S A LARGE NUMBER OF NF 2069 01:48:56,480 --> 01:49:00,200 1 MUTATIONS THAT CAN OCCUR BUT I 2070 01:49:00,200 --> 01:49:02,480 THINK THE SECOND ONE WOULD BE 2071 01:49:02,480 --> 01:49:04,120 REALLY THE CONSEQUENCE BECAUSE 2072 01:49:04,120 --> 01:49:15,640 WE HAVE PEOPLE WITH NF 1 WHO 2073 01:49:15,640 --> 01:49:20,080 GROW UP AND LIKE OUR PATIENT WHO 2074 01:49:20,080 --> 01:49:22,280 ARE INTELLIGENT AND SOME ARE 2075 01:49:22,280 --> 01:49:23,240 SEVERELY AFFECTED. 2076 01:49:23,240 --> 01:49:28,920 AND THERE'S A SUCH A BROAD 2077 01:49:28,920 --> 01:49:48,080 SPECTR 2078 01:49:48,080 --> 01:49:48,440 SPECTRUM. 2079 01:49:48,440 --> 01:49:49,840 >> WE HAVE A PERSONAL QUESTION 2080 01:49:49,840 --> 01:49:51,120 FOR YOU. 2081 01:49:51,120 --> 01:49:54,160 HOW DID YOU BECOME INTERESTED IN 2082 01:49:54,160 --> 01:49:54,840 THE STUDY? 2083 01:49:54,840 --> 01:50:00,560 >> IT'S NOT REALLY COOL BUT IT 2084 01:50:00,560 --> 01:50:01,680 WAS BECAUSE I KNEW THERE WERE 2085 01:50:01,680 --> 01:50:03,240 DRUGS OUT THAT TARGET RAS AND WE 2086 01:50:03,240 --> 01:50:08,480 THOUGHT THIS IS GOING TO BE 2087 01:50:08,480 --> 01:50:13,880 HELPFUL FOR THESE PATIENTS AND 2088 01:50:13,880 --> 01:50:16,840 WE ENROLLED PATIENTS IN 2089 01:50:16,840 --> 01:50:18,040 TREATMENT TRIALS. 2090 01:50:18,040 --> 01:50:20,240 I THOUGHT THIS IS GOING TO BE AN 2091 01:50:20,240 --> 01:50:22,360 EASY THING. 2092 01:50:22,360 --> 01:50:25,000 WE HAVE TRANSFERASE INHIBITERS 2093 01:50:25,000 --> 01:50:26,320 THAT BLOCK ACTIVATION. 2094 01:50:26,320 --> 01:50:31,760 IT SEEMED SO LOGICAL TO TRY AND 2095 01:50:31,760 --> 01:50:41,960 THIS REALLY THEN I LEARNED IT'S 2096 01:50:41,960 --> 01:50:44,600 NOT AS EASY AS I THOUGHT AND THE 2097 01:50:44,600 --> 01:50:46,720 RELATIONSHIP WE ESTABLISHED WITH 2098 01:50:46,720 --> 01:50:48,840 OUR PATIENTS HAS HELPED SUSTAIN 2099 01:50:48,840 --> 01:50:49,040 THIS. 2100 01:50:49,040 --> 01:50:51,360 THEY STAY WITH US FOR YEARS. 2101 01:50:51,360 --> 01:50:52,840 I HAVE KIDS THAT WERE 3 YEARS 2102 01:50:52,840 --> 01:50:59,200 OLD AND NOW 23 YEARS OLD. 2103 01:50:59,200 --> 01:51:02,360 ONCE YOU GET INTO THE FIELD YOU 2104 01:51:02,360 --> 01:51:04,200 GET HOOKED. 2105 01:51:04,200 --> 01:51:07,760 AND NOW DR. SHERNA IS HOOKED TOO 2106 01:51:07,760 --> 01:51:08,840 BECAUSE HE'LL HOPEFULLY MAKE THE 2107 01:51:08,840 --> 01:51:13,200 PROGRESS WE FAILED TO MAKE TO 2108 01:51:13,200 --> 01:51:17,880 DATE. 2109 01:51:17,880 --> 01:51:19,960 >> THE PROGRESS JACK DESCRIBED 2110 01:51:19,960 --> 01:51:20,840 IS BREATHTAKING IN ITS 2111 01:51:20,840 --> 01:51:28,120 POTENTIAL. 2112 01:51:28,120 --> 01:51:29,560 IF I'D BE SMARTER AND YOUNGER 2113 01:51:29,560 --> 01:51:31,160 I'D APPLY TO BE A POST-DOC IN 2114 01:51:31,160 --> 01:51:46,760 HIS LAB. 2115 01:51:46,760 --> 01:51:48,040 >> I'LL TAKE YOU. 2116 01:51:48,040 --> 01:51:52,280 >> THIS HAS OPENED UP A 2117 01:51:52,280 --> 01:51:56,920 PANDORA'S BOX OF POSSIBILITIES 2118 01:51:56,920 --> 01:51:58,600 AND PATIENTS WHO HAD LITTLE 2119 01:51:58,600 --> 01:52:00,280 INFORMATION OF THE DISEASE AND 2120 01:52:00,280 --> 01:52:02,880 TREATMENT, I ASSUME IT'S ALSO A 2121 01:52:02,880 --> 01:52:06,080 GLOBAL IF NOT NATIONAL EFFORT. 2122 01:52:06,080 --> 01:52:11,680 MAYBE YOU WOULD EXPLAIN HOW YOU 2123 01:52:11,680 --> 01:52:21,680 GO FROM BEING SINGLE LAB AND 2124 01:52:21,680 --> 01:52:22,840 DEALING WITH A RARE DISEASE ALL 2125 01:52:22,840 --> 01:52:26,880 OVER THE WORLD. 2126 01:52:26,880 --> 01:52:29,440 HOW DO YOU GO ABOUT MARSHALLING 2127 01:52:29,440 --> 01:52:31,080 ALL THE OPPORTUNITIES AND 2128 01:52:31,080 --> 01:52:32,920 TALENTS THAT EXIST AND WHAT ARE 2129 01:52:32,920 --> 01:52:44,280 THE MECHANISMS USED TO BRING 2130 01:52:44,280 --> 01:52:45,280 THIS COMMUNITY TOGETHER AND IS 2131 01:52:45,280 --> 01:52:48,920 THERE SUPPORT FOR IT? 2132 01:52:48,920 --> 01:52:51,480 >> BRIGITTE IS A MASTER OF 2133 01:52:51,480 --> 01:52:52,160 COLLABORATIONS AND I SORT OF 2134 01:52:52,160 --> 01:52:54,240 LEARN FROM HER. 2135 01:52:54,240 --> 01:52:55,560 I THINK THIS COMMUNITY THERE'S 2136 01:52:55,560 --> 01:52:56,880 SOMETHING UNIQUE ABOUT THE 2137 01:52:56,880 --> 01:53:12,880 COMMUNITY. 2138 01:53:12,880 --> 01:53:15,440 IT ATTRACTS PEOPLE WHO ARE 2139 01:53:15,440 --> 01:53:16,240 CREATIVE AND COLLABORATIVE AND 2140 01:53:16,240 --> 01:53:18,400 YOU DON'T FIND THAT IN EVERY 2141 01:53:18,400 --> 01:53:19,640 DISEASE TYPE BUT THIS PARTICULAR 2142 01:53:19,640 --> 01:53:37,320 ONE IS A REMARKABLE THING AND 2143 01:53:37,320 --> 01:53:40,920 THE CONFERENCE THEY STARTED AND 2144 01:53:40,920 --> 01:53:42,520 THE PEOPLE WHO BLOCKED TO THIS 2145 01:53:42,520 --> 01:53:44,800 AND IT'S AN INTERNATIONAL 2146 01:53:44,800 --> 01:53:45,120 COLLABORATION. 2147 01:53:45,120 --> 01:53:46,240 WE HAVE ANNUAL MEETINGS WHERE 2148 01:53:46,240 --> 01:53:48,920 PEOPLE FROM ALL OVER THE WORLD 2149 01:53:48,920 --> 01:53:49,120 COME. 2150 01:53:49,120 --> 01:53:50,600 IT'S COMPETITIVE FIELD. 2151 01:53:50,600 --> 01:53:53,520 IT'S GOTTEN MORE COMPETITIVE. 2152 01:53:53,520 --> 01:53:55,720 OUR ADVANTAGE HERE I THINK AT 2153 01:53:55,720 --> 01:53:58,960 THE CLINICAL CENTER IS WE INDEED 2154 01:53:58,960 --> 01:54:03,040 CAN DO WHOLE BODY MRIs THAT COST 2155 01:54:03,040 --> 01:54:05,880 $10,000 AT THE OUTSET, IT 2156 01:54:05,880 --> 01:54:08,480 SHOULDN'T BUT DOES AND THE 2157 01:54:08,480 --> 01:54:11,200 LUXURY WE FOLLOW PATIENTS 2158 01:54:11,200 --> 01:54:12,160 METICULOUSLY AND HAVE BASIC 2159 01:54:12,160 --> 01:54:13,560 COLLABORATORS AT THE SAME TIME 2160 01:54:13,560 --> 01:54:16,560 AND THIS GAVE US THE ADVANTAGE 2161 01:54:16,560 --> 01:54:18,960 WHEN WE DEVELOPED OUR CLINICAL 2162 01:54:18,960 --> 01:54:20,240 TRIALS BUT WITHOUT THE PATIENTS 2163 01:54:20,240 --> 01:54:22,680 BEING COMMITTED TO SAYING YES, 2164 01:54:22,680 --> 01:54:26,320 I'LL COME FOR THIS MEDICINE I 2165 01:54:26,320 --> 01:54:28,080 GET EVERY FOUR MONTHS AN MRI AND 2166 01:54:28,080 --> 01:54:30,120 SLEEP STUDY AND RANGE OF MOTION 2167 01:54:30,120 --> 01:54:33,760 STUDY AND ALL THE QUESTIONNAIRES 2168 01:54:33,760 --> 01:54:36,920 WE WOULD NOT HAVE AN FDA 2169 01:54:36,920 --> 01:54:40,920 APPROVAL FOR TREATMENT. 2170 01:54:40,920 --> 01:54:44,680 THAT'S WONDERFUL. 2171 01:54:44,680 --> 01:54:46,040 IT'S VERY EXCITING. 2172 01:54:46,040 --> 01:54:48,440 ON BEHALF OF I'M SURE A LARGE 2173 01:54:48,440 --> 01:54:50,280 NUMBER OF PEOPLE WHO ARE TUNED 2174 01:54:50,280 --> 01:54:55,720 IN AROUND THE WORLD THAT I THINK 2175 01:54:55,720 --> 01:54:59,480 I'M NOT OUD OF OUT OF LINE TO 2176 01:54:59,480 --> 01:55:00,680 EXPRESSING OUR GRATITUDE TO YOU 2177 01:55:00,680 --> 01:55:04,440 YOU AND HEATHER AND ADMIRATION 2178 01:55:04,440 --> 01:55:08,880 FOR THE TENACITY, CREATIVITY AND 2179 01:55:08,880 --> 01:55:11,280 HOPE THAT YOU BRING TO THIS 2180 01:55:11,280 --> 01:55:11,600 FIELD. 2181 01:55:11,600 --> 01:55:12,880 SO THANK YOU. 2182 01:55:12,880 --> 00:00:00,000 THANK YOU VERY MUCH.