1 00:00:06,099 --> 00:00:08,568 >> GOOD AFTERNOON AND WELCOME TO 2 00:00:08,568 --> 00:00:11,304 TODAY'S CLINICAL CENTER GRAND 3 00:00:11,304 --> 00:00:16,409 ROUNDS THE CODE IS 57908. 4 00:00:16,409 --> 00:00:18,611 TIME THIS TO THE JOHNS HOPKINS 5 00:00:18,611 --> 00:00:19,712 PHONE NUMBER SHOWN ON THE SLIDE. 6 00:00:19,712 --> 00:00:23,683 WE CURRENTLY INVITE YOU TO 7 00:00:23,683 --> 00:00:25,218 PROVIDE FEEDBACK BY SCANNING THE 8 00:00:25,218 --> 00:00:27,053 QR CODE ON THE SLIDE. 9 00:00:27,053 --> 00:00:30,023 FOR THOSE APPLYING FOR CME 10 00:00:30,023 --> 00:00:37,030 YOU'LL RECEIVE A SURVEY AND IT 11 00:00:37,030 --> 00:00:40,934 ALLOWS SUGGESTIONS FOR FUTURE 12 00:00:40,934 --> 00:00:42,969 GRAND ROUNDS TOPICS. 13 00:00:42,969 --> 00:00:43,536 FOLLOWING THE PRESENTATION 14 00:00:43,536 --> 00:00:47,006 QUESTIONS WILL BE TAKEN FROM THE 15 00:00:47,006 --> 00:00:50,043 AISLES. 16 00:00:50,043 --> 00:00:52,445 ADDITI 17 00:00:52,445 --> 00:00:54,047 ADDITIONALLY, VIDEOCAST VIEWERS 18 00:00:54,047 --> 00:00:57,817 CAN SUBMIT DURING THE SEND LIVE 19 00:00:57,817 --> 00:01:00,119 FEEDBACK WITH AT THE END OF THE 20 00:01:00,119 --> 00:01:00,486 PRESENTATION. 21 00:01:00,486 --> 00:01:06,025 WE'LL HONORED WITH OUR SPEAKER, 22 00:01:06,025 --> 00:01:11,364 DR. SHEPPARD FROM THE EUNICE 23 00:01:11,364 --> 00:01:12,232 KENNEDY SHRIVER CENTER FOR CHILD 24 00:01:12,232 --> 00:01:16,603 HEALTH AND HUMAN DEVELOPMENT. 25 00:01:16,603 --> 00:01:18,504 SHE'S EARNED HER DEGREE FROM THE 26 00:01:18,504 --> 00:01:19,372 MASSACHUSETTS INSTITUTE OF 27 00:01:19,372 --> 00:01:21,207 TECHNOLOGY AND MEDICAL DEGREE 28 00:01:21,207 --> 00:01:24,277 AND DOCTORATE IN GENETICS AND 29 00:01:24,277 --> 00:01:26,613 BIO INFORMATICS AT THE 30 00:01:26,613 --> 00:01:29,482 UNIVERSITY OF MASSACHUSETTS 31 00:01:29,482 --> 00:01:31,317 MEDICAL SCHOOL. 32 00:01:31,317 --> 00:01:35,588 DR. SHEPPARD THEN COMPLETED 33 00:01:35,588 --> 00:01:37,123 CLINICAL GENETICS AT THE 34 00:01:37,123 --> 00:01:39,993 CHILDREN'S HOSPITAL PHILADELPHIA 35 00:01:39,993 --> 00:01:46,032 AND JOINED AS A CLINICAL 36 00:01:46,032 --> 00:01:53,139 GENETICISTS AND WHILE AT CHOC 37 00:01:53,139 --> 00:01:54,340 SHE COMPLETED AT THE UNIVERSITY 38 00:01:54,340 --> 00:01:56,542 OF PENNSYLVANIA PULLMAN'S SCHOOL 39 00:01:56,542 --> 00:01:59,045 OF MEDICINE AND POSTDOCTORAL 40 00:01:59,045 --> 00:02:06,019 FELLOWSHIP AT CHOC FOCUSSING ON 41 00:02:06,019 --> 00:02:10,123 IMPROVED DIAGNOSTICS AND SHE 42 00:02:10,123 --> 00:02:13,326 JOINED THE NIH AT NICHD AND THE 43 00:02:13,326 --> 00:02:14,627 FOCUS OF HER TRANSLATIONAL 44 00:02:14,627 --> 00:02:17,797 RESEARCH GROUP IS TO DEVELOP 45 00:02:17,797 --> 00:02:18,931 MORE EFFICACIOUS THERAPIES FOR 46 00:02:18,931 --> 00:02:21,934 PATIENTS WITH MALFORMATIONS OF 47 00:02:21,934 --> 00:02:22,969 THE LYMPHATIC SYSTEM. 48 00:02:22,969 --> 00:02:24,937 SHE'S A PROLIFIC INVESTIGATOR 49 00:02:24,937 --> 00:02:27,240 AND BOARD CERTIFIED BY BOTH THE 50 00:02:27,240 --> 00:02:28,241 AMERICAN BOARD OF AMERICAN 51 00:02:28,241 --> 00:02:31,344 GENETICS AND GENOMICS AND THE 52 00:02:31,344 --> 00:02:41,054 AMERICAN BOARD OF PEDIATRICS AND 53 00:02:41,054 --> 00:02:47,794 CO-AUTHORED PIER REVIEWED 54 00:02:47,794 --> 00:02:50,396 ARTICLES AND RECEIVED MANY 55 00:02:50,396 --> 00:02:53,733 AWARDS AS THE AUTHOR OF THE MOST 56 00:02:53,733 --> 00:02:55,768 SIGNIFICANT CONTRIBUTION TO THE 57 00:02:55,768 --> 00:02:58,771 AMERICAN JOURNAL OF GENETICS BY 58 00:02:58,771 --> 00:03:00,239 A JUNIOR INVESTIGATOR. 59 00:03:00,239 --> 00:03:10,783 HER TITLE IS GENOMICS INFORMED 60 00:03:12,518 --> 00:03:13,219 PRECISION MEDICINE FOR 61 00:03:13,219 --> 00:03:16,255 INDIVIDUALS WITH LYMPHATIC 62 00:03:16,255 --> 00:03:16,522 ANOMALIES. 63 00:03:16,522 --> 00:03:18,124 >> THANK YOU SO MUCH FOR THE 64 00:03:18,124 --> 00:03:27,700 VERY KIND INTRODUCTION. 65 00:03:27,700 --> 00:03:29,635 THESE ARE MY DISCLOSURES AND 66 00:03:29,635 --> 00:03:31,537 THIS PATIENT WAS BORN AFTER A 67 00:03:31,537 --> 00:03:36,109 PREGNANCY WITH MULTIPLE 68 00:03:36,109 --> 00:03:37,276 CONGENITAL ANOMALIES AND THIS IS 69 00:03:37,276 --> 00:03:41,981 A PHOTOGRAPH OF HIM AFTER BIRTH. 70 00:03:41,981 --> 00:03:46,018 DURING PREGNANCY HE HAD AN 71 00:03:46,018 --> 00:03:46,753 IRREGULAR HEARTBEAT AND THOUGH 72 00:03:46,753 --> 00:03:49,155 THIS WAS TRYING TO BE CONTROLLED 73 00:03:49,155 --> 00:03:51,290 HE DEVELOPED SWELLING IN 74 00:03:51,290 --> 00:03:53,960 MULTIPLE BODY COMPARTMENTS KNOWN 75 00:03:53,960 --> 00:03:59,499 AS NON-IMMUNE FETAL HIDROX AND 76 00:03:59,499 --> 00:04:03,136 WAS BORN PREMATURELY AND YOU CAN 77 00:04:03,136 --> 00:04:06,038 SEE HE REQUIRES VENTILATION 78 00:04:06,038 --> 00:04:10,009 SUPPORT AND SEE THE MALFORMATION 79 00:04:10,009 --> 00:04:16,849 S INCLUDING THE SKIN COLORED 80 00:04:16,849 --> 00:04:20,353 PLAQUES AND A PATTERN ON HIS 81 00:04:20,353 --> 00:04:20,987 BODY. 82 00:04:20,987 --> 00:04:25,992 THE EYELID COLOBOMA AND 83 00:04:25,992 --> 00:04:33,566 PAPILLOMA EYELID AND POST SET 84 00:04:33,566 --> 00:04:37,470 EARS AND AFTER ARRHYTHMIA HE 85 00:04:37,470 --> 00:04:39,972 CONTINUED TO HAVE ISSUES WITH 86 00:04:39,972 --> 00:04:42,008 FLUID IN THE ABDOMEN AND FLUID 87 00:04:42,008 --> 00:04:43,543 AROUND THE LUNGS AND IT WAS 88 00:04:43,543 --> 00:04:47,213 SUSPECTED HE HAD A PROBLEM WITH 89 00:04:47,213 --> 00:04:49,282 HIS LYMPHATIC VASCULATURE. 90 00:04:49,282 --> 00:04:51,584 THE LYMPHATICS HAVE THREE 91 00:04:51,584 --> 00:04:51,851 FUNCTIONS. 92 00:04:51,851 --> 00:04:54,854 TO ABSORB PROTEIN RICH FLUID 93 00:04:54,854 --> 00:04:57,423 FROM THE TISSUES AND TRANSFER IT 94 00:04:57,423 --> 00:04:59,225 BACK TO THE BLOOD VASCULAR 95 00:04:59,225 --> 00:05:04,297 SYSTEM AND ABSORB FAT AND 96 00:05:04,297 --> 00:05:06,399 TRANSPORT IMMUNE CELLS AND IF WE 97 00:05:06,399 --> 00:05:09,702 SUSPECT SOMEONE HAS A PROBLEM 98 00:05:09,702 --> 00:05:11,904 PATIENTS CAN HAVE CONTRAST 99 00:05:11,904 --> 00:05:15,675 INJECTED BY LYMPH NODES AND 100 00:05:15,675 --> 00:05:16,309 INTERNODAL IMAGES THROUGH THE 101 00:05:16,309 --> 00:05:19,312 MESS EN TERRY OR LIVER 102 00:05:19,312 --> 00:05:22,014 LYMPHATICS AND THE PATIENTS ARE 103 00:05:22,014 --> 00:05:24,417 IMAGED BY MRI TO EVALUATE THE 104 00:05:24,417 --> 00:05:26,486 CENTRAL FLOW PATTERN. 105 00:05:26,486 --> 00:05:27,553 IN A TYPICAL PATIENT THIS IS 106 00:05:27,553 --> 00:05:29,021 WHAT YOU MIGHT SEE. 107 00:05:29,021 --> 00:05:35,228 THIS IS THE THORACIC DUCT HERE 108 00:05:35,228 --> 00:05:38,664 WITH THE LIVER INJECTION THEY'RE 109 00:05:38,664 --> 00:05:39,732 NICE THIN VESSELS. 110 00:05:39,732 --> 00:05:41,567 IN CONTRAST IN OUR PATIENT, THE 111 00:05:41,567 --> 00:05:46,005 CENTRAL LYMPHATIC IMAGING SHOWED 112 00:05:46,005 --> 00:05:47,573 CENTRAL LYMPHATIC CONDUCTING 113 00:05:47,573 --> 00:05:50,243 ANOMALY MALFORM S WHERE WE KNOW 114 00:05:50,243 --> 00:05:52,478 THE CENTRAL LYMPHATIC FLOW IS 115 00:05:52,478 --> 00:05:54,046 COMPLETELY ABNORMAL. 116 00:05:54,046 --> 00:05:57,917 IN CONTRAST TO A TYPICAL HUMAN, 117 00:05:57,917 --> 00:05:59,719 WE CAN SEE IN OUR PATIENT 118 00:05:59,719 --> 00:06:01,621 THERE'S A TON OF CONTRAST 119 00:06:01,621 --> 00:06:06,626 SPILLING OUT HERE INTO THE RETRO 120 00:06:06,626 --> 00:06:10,029 PER I TIN YUM AND IN THE LIVER 121 00:06:10,029 --> 00:06:13,432 INJECTION YOU CAN SEE THE 122 00:06:13,432 --> 00:06:18,504 SPILLING OF ABDOMINAL 123 00:06:18,504 --> 00:06:20,540 MALFORMATION AND PROFUSION INTO 124 00:06:20,540 --> 00:06:21,073 THE LUNGS. 125 00:06:21,073 --> 00:06:24,076 THE TREATMENT FOR THE PATIENTS 126 00:06:24,076 --> 00:06:27,246 ARE MOSTLY SYMPTOMATIC AND WE 127 00:06:27,246 --> 00:06:29,782 HAVE WHERE LYMPHATICS CAN BE 128 00:06:29,782 --> 00:06:33,219 CONNECTED TO VEINS TO ALLEVIATE 129 00:06:33,219 --> 00:06:35,388 SOME PRESSURE AND ASSIST WITH 130 00:06:35,388 --> 00:06:37,757 DRAINING AND MEDICAL GRADE SUPER 131 00:06:37,757 --> 00:06:40,760 GLUE CAN BE INJECTED INTO LEAKY 132 00:06:40,760 --> 00:06:43,029 VESSELS AND MEDICINES I'LL TELL 133 00:06:43,029 --> 00:06:43,863 YOU A LITTLE BIT MORE ABOUT 134 00:06:43,863 --> 00:06:45,932 TODAY WHICH ARE MORE COMMONLY IN 135 00:06:45,932 --> 00:06:49,402 USE TODAY THAN AT THE TIME THIS 136 00:06:49,402 --> 00:06:50,836 PATIENT WAS BORN. 137 00:06:50,836 --> 00:06:52,338 UNFORTUNATELY HE PASSED AWAY AS 138 00:06:52,338 --> 00:06:55,308 YOU CAN SEE HIS MALL FORMATIONS 139 00:06:55,308 --> 00:07:00,479 WERE VERY DIFFUSE AND WASN'T 140 00:07:00,479 --> 00:07:03,249 REALLY ELIGIBLE FOR THESE 141 00:07:03,249 --> 00:07:06,485 TREATMENTS AND IT DROVE HOME TO 142 00:07:06,485 --> 00:07:09,822 ME HOW DO DELIVER PERSONALIZED 143 00:07:09,822 --> 00:07:13,359 TREATMENT AND MALFORMATIONS CAN 144 00:07:13,359 --> 00:07:15,695 CAUSE SIGNIFICANT DISABILITY. 145 00:07:15,695 --> 00:07:18,831 EVEN SIMPLE LYMPHATIC 146 00:07:18,831 --> 00:07:25,404 MALFORMALITIES CAN CAUSE LARGE 147 00:07:25,404 --> 00:07:27,473 PROBLEMS AND PEDIATRIC 148 00:07:27,473 --> 00:07:30,676 LYMPHEDEMA WHERE PATIENTS HAVE 149 00:07:30,676 --> 00:07:32,745 SWOLEN LIMBS OR COMPLEX 150 00:07:32,745 --> 00:07:36,616 LYMPHATIC ANOMALIES WHICH IS 151 00:07:36,616 --> 00:07:37,950 BUCKET TERM FOR FOUR DISORDERS 152 00:07:37,950 --> 00:07:40,086 WHERE THERE'S MALFORMATIONS 153 00:07:40,086 --> 00:07:43,122 THROUGHOUT THE BODY INCLUDING 154 00:07:43,122 --> 00:07:44,991 CENTRAL CONDUCTING ANOMALY WHERE 155 00:07:44,991 --> 00:07:49,128 THERE'S ABNORMAL FLOW IN THE 156 00:07:49,128 --> 00:07:51,564 CENTRAL LYMPHATICS AND GENETIC 157 00:07:51,564 --> 00:07:53,866 ANOMALY WHERE WE SEE 158 00:07:53,866 --> 00:07:54,967 MALFORMATIONS IN THE BONE AND 159 00:07:54,967 --> 00:07:57,169 SPLEEN AND WHERE WE SEE 160 00:07:57,169 --> 00:08:04,043 MALFORMATIONS IN THE BONE, MEDIA 161 00:08:04,043 --> 00:08:06,946 STINUM AND THEY OCCUR IN 1 IN 162 00:08:06,946 --> 00:08:08,481 4,000 LIVE BIRTHS. 163 00:08:08,481 --> 00:08:09,649 WHEN WE THINK OF THE CURRENT 164 00:08:09,649 --> 00:08:10,616 LIMITATIONS FOR DIAGNOSIS AND 165 00:08:10,616 --> 00:08:12,018 TREATMENT FOR THESE PATIENTS 166 00:08:12,018 --> 00:08:15,321 IT'S SIMILAR TO THAT OF OTHER 167 00:08:15,321 --> 00:08:16,889 RARE DISORDERS. 168 00:08:16,889 --> 00:08:19,892 MANY ARE RARE AND HETEROGENEOUS 169 00:08:19,892 --> 00:08:22,028 ESPECIALLY THESE COMPLEX 170 00:08:22,028 --> 00:08:24,997 LYMPHATIC ANOMALIES AND CAN 171 00:08:24,997 --> 00:08:25,998 RESULT IN THIS DIAGNOSIS. 172 00:08:25,998 --> 00:08:27,667 WE HAVE A LIMITED UNDERSTAND OF 173 00:08:27,667 --> 00:08:28,601 THESE DISORDERS BUT I'LL TELL 174 00:08:28,601 --> 00:08:30,002 YOU ABOUT THE GROUP MY WORK HAS 175 00:08:30,002 --> 00:08:31,737 DONE TO IMPROVE THIS. 176 00:08:31,737 --> 00:08:33,406 FINALLY, WE HAVE FEW MEDICAL 177 00:08:33,406 --> 00:08:35,374 TREATMENTS THAT TARGET THE 178 00:08:35,374 --> 00:08:37,810 UNDERLYING CAUSE WITH ONLY ONE 179 00:08:37,810 --> 00:08:38,377 MEDICINE THAT'S FDA 180 00:08:38,377 --> 00:08:39,011 CONDITIONALLY APPROVED AT THIS 181 00:08:39,011 --> 00:08:49,121 TIME. 182 00:08:54,093 --> 00:08:55,528 ALIGNING WITH THE STRATEGIC PLAN 183 00:08:55,528 --> 00:09:01,000 TO IDENTIFY GENOMIC CHANGE TO 184 00:09:01,000 --> 00:09:08,374 EXPLAIN OR PREDICT FETAL 185 00:09:08,374 --> 00:09:10,376 CONDITIONS AND TO FURTHER THE 186 00:09:10,376 --> 00:09:12,278 UNDERSTANDING OF THE CELLULAR 187 00:09:12,278 --> 00:09:13,979 AND STRUCTURAL BASIS THROUGH 188 00:09:13,979 --> 00:09:15,881 WHAT WE KNOW ABOUT THIS DISEASE 189 00:09:15,881 --> 00:09:19,819 MODELS AND TO ADVANCE GENOMICS 190 00:09:19,819 --> 00:09:26,225 TO ADVANCE EFFECTIVE AND SAFE 191 00:09:26,225 --> 00:09:28,694 THERAPEUTICS FOR CHILDREN. 192 00:09:28,694 --> 00:09:31,430 WHEN WE BREAK IT DOWN TO TREAT A 193 00:09:31,430 --> 00:09:32,231 PATIENT BASED ON THEIR PHENOTYPE 194 00:09:32,231 --> 00:09:36,001 WE NEED TO MAKE SURE WE CAN HAVE 195 00:09:36,001 --> 00:09:37,069 A TRUE DIAGNOSIS. 196 00:09:37,069 --> 00:09:38,971 WE ALSO NEED AN UNDERSTANDING OF 197 00:09:38,971 --> 00:09:40,740 THE MOLECULAR PATHOGENESIS AND 198 00:09:40,740 --> 00:09:43,442 FINALLY WE NEED TO ACTUALLY 199 00:09:43,442 --> 00:09:46,011 UNDERSTAND HOW THAT TREATMENT 200 00:09:46,011 --> 00:09:52,384 AFFECTS PATIENT OUTCOMES. 201 00:09:52,384 --> 00:09:54,019 TODAY I'LL TALK ABOUT THE STEPS 202 00:09:54,019 --> 00:09:57,723 MY LAB HAS TAKEN AND THE GENETIC 203 00:09:57,723 --> 00:09:59,425 TESTING FOR THIS PATIENT POMP 204 00:09:59,425 --> 00:10:00,392 AND ESTABLISHMENT OF THE NATURAL 205 00:10:00,392 --> 00:10:03,262 HISTORY STUDY AT THE NIH 206 00:10:03,262 --> 00:10:04,764 CLINICAL CENTER IN COLLABORATION 207 00:10:04,764 --> 00:10:06,165 PROBABLY WITH MANY IN THE 208 00:10:06,165 --> 00:10:09,368 AUDIENCE AND MANY WATCHING 209 00:10:09,368 --> 00:10:09,668 ONLINE. 210 00:10:09,668 --> 00:10:12,938 I'LL TALK BRIEFLY ABOUT OUR WORK 211 00:10:12,938 --> 00:10:14,840 WITH K RAS RELATED ANOMALIES IN 212 00:10:14,840 --> 00:10:17,910 THE LAB AND HOW THIS HAS LED TO 213 00:10:17,910 --> 00:10:20,579 THE TRANSITION OF PATIENTS TO 214 00:10:20,579 --> 00:10:22,915 OFF LABEL AND WHY BASED ON WHAT 215 00:10:22,915 --> 00:10:24,483 WE KNOW WE STILL NEED TO WORK 216 00:10:24,483 --> 00:10:25,484 FURTHER TO UNDER THE WHAT OUR 217 00:10:25,484 --> 00:10:26,385 NOVEL THERAPIES WE CAN USE TO 218 00:10:26,385 --> 00:10:31,323 TREAT THESE PATIENTS. 219 00:10:31,323 --> 00:10:33,425 WHEN WE THINK OF IMPROVING THE 220 00:10:33,425 --> 00:10:35,261 DIAGNOSIS WE'RE THINKING OF TWO 221 00:10:35,261 --> 00:10:37,396 THINGS, PHENOTYPES OR THE 222 00:10:37,396 --> 00:10:39,832 CLINICAL SYSTEMS PATIENTS HAVE 223 00:10:39,832 --> 00:10:40,933 AS WELL AS GENOTYPES OR THE 224 00:10:40,933 --> 00:10:42,034 GENETIC CAUSES. 225 00:10:42,034 --> 00:10:43,602 WE'RE REALLY ASKING THREE MAJOR 226 00:10:43,602 --> 00:10:44,904 QUESTIONS. 227 00:10:44,904 --> 00:10:46,705 SO WHAT ARE THESE PHENOTYPES AND 228 00:10:46,705 --> 00:10:48,307 GENOTYPES THAT DEFINE DISEASE. 229 00:10:48,307 --> 00:10:50,576 HOW DO THESE DISORDERS EVOLVE OR 230 00:10:50,576 --> 00:10:53,846 CHANGE OVER TIME, AND THEN WHAT 231 00:10:53,846 --> 00:10:55,481 BIOMARKERS OR OTHER CLINICAL 232 00:10:55,481 --> 00:10:57,883 RESPONSE MEASURES CAN BE USED TO 233 00:10:57,883 --> 00:11:01,220 MONITOR DISEASE PROGRESSION AND 234 00:11:01,220 --> 00:11:01,487 RESPONSE? 235 00:11:01,487 --> 00:11:03,155 AND SO FIRST WHEN WE STARTED 236 00:11:03,155 --> 00:11:06,058 THIS WORK THERE WERE VERY LITTLE 237 00:11:06,058 --> 00:11:07,493 KNOWN CAUSES FOR THESE RARE 238 00:11:07,493 --> 00:11:09,728 GENETIC DISORDERS CALLED CENTRAL 239 00:11:09,728 --> 00:11:12,198 CONDUCTING LYMPHATIC ANOMALY. 240 00:11:12,198 --> 00:11:13,265 I'LL SHOW THE FIGURE THROUGHOUT 241 00:11:13,265 --> 00:11:16,001 THE TALK AND SO I WANT TO ORIENT 242 00:11:16,001 --> 00:11:17,570 YOU. 243 00:11:17,570 --> 00:11:22,641 WE KNOW BOTH THE KINASE AND RAS 244 00:11:22,641 --> 00:11:24,043 SIGNALLING PATHWAY ARE IMPORTANT 245 00:11:24,043 --> 00:11:26,011 FOR VASCULAR DEVELOPMENT. 246 00:11:26,011 --> 00:11:28,581 WE SEE A GROWTH FACTOR BINDING 247 00:11:28,581 --> 00:11:35,287 TO THE KINASE LEADING TO THE AKT 248 00:11:35,287 --> 00:11:36,155 MFOR OR RAS SIGNALLING. 249 00:11:36,155 --> 00:11:40,125 AND WHEN I FIRST STARTED THE 250 00:11:40,125 --> 00:11:44,196 WORK IN MY POSTDOCTORAL 251 00:11:44,196 --> 00:11:46,599 FELLOWSHIP WE ONLY KNEW TWO 252 00:11:46,599 --> 00:11:47,099 CAUSES. 253 00:11:47,099 --> 00:11:53,072 ONE WAS A RECEPTOR KINASE AND 254 00:11:53,072 --> 00:11:53,739 ONE OTHER. 255 00:11:53,739 --> 00:11:55,641 THE FIRST STEP WE DID WAS LOOK 256 00:11:55,641 --> 00:12:01,547 IN A COHORT OF PATIENTS IN A 257 00:12:01,547 --> 00:12:03,616 SINGLE CENTER STUDY TO 258 00:12:03,616 --> 00:12:04,717 UNDERSTAND WHAT WERE THE GENETIC 259 00:12:04,717 --> 00:12:05,150 CAUSES. 260 00:12:05,150 --> 00:12:09,021 SO THIS IS THE LARGEST COHORT TO 261 00:12:09,021 --> 00:12:11,423 DAY AND WERE ABILITY TO IDENTIFY 262 00:12:11,423 --> 00:12:13,092 11 NEW GENETIC CAUSES. 263 00:12:13,092 --> 00:12:18,063 THE MAJORITY LED TO 264 00:12:18,063 --> 00:12:21,000 DYSREGULATION OF RAS PATHWAY 265 00:12:21,000 --> 00:12:21,300 SIGNALLING. 266 00:12:21,300 --> 00:12:25,070 AS A GENETICISTS WE'RE ALWAYS 267 00:12:25,070 --> 00:12:27,106 LOOKING TO CLUES TO PINPOINT 268 00:12:27,106 --> 00:12:28,073 DIAGNOSIS. 269 00:12:28,073 --> 00:12:31,043 WE THINK OF THESE AS UNIQUE OR 270 00:12:31,043 --> 00:12:32,111 OFFICIAL FEATURES AND WONDERED 271 00:12:32,111 --> 00:12:35,314 IF WE COULD DO THIS WITH THE 272 00:12:35,314 --> 00:12:35,881 CENTRAL LYMPHATICS AS WELL. 273 00:12:35,881 --> 00:12:37,549 INDEED THAT'S WHAT WE FOUND. 274 00:12:37,549 --> 00:12:41,053 HERE ARE CENTRAL LYMPHATIC 275 00:12:41,053 --> 00:12:42,054 IMAGING. 276 00:12:42,054 --> 00:12:43,956 CENTRAL LYMPHATIC IMAGES OF 277 00:12:43,956 --> 00:12:45,724 PATIENTS WITH THREE DIFFERENT 278 00:12:45,724 --> 00:12:50,329 GENETIC DISORDERS. 279 00:12:50,329 --> 00:12:53,799 PTPN11 LEADS TO DYSREGULATION OF 280 00:12:53,799 --> 00:12:57,903 THE RAS PATHWAY AND WHAT WE SEE 281 00:12:57,903 --> 00:13:06,779 IS THIS POSTERIOR THORACIC FLOW 282 00:13:06,779 --> 00:13:10,883 AND INDIVIDUALS WITH TRISOMY 21 283 00:13:10,883 --> 00:13:13,819 HAVE THESE DILATED VESSELS IN 284 00:13:13,819 --> 00:13:16,755 THE PAIN AND NECK AND WHEN YOU 285 00:13:16,755 --> 00:13:18,757 LOOK AT THE PREGNANCY SCREENING 286 00:13:18,757 --> 00:13:22,061 FOR DOWN SYNDROME AND OTHER 287 00:13:22,061 --> 00:13:25,564 CHROMOSOMAL ABNORMALITY SEEING 288 00:13:25,564 --> 00:13:29,101 THIS MAKES SENSE AND PIEZ01 WE 289 00:13:29,101 --> 00:13:32,371 SEE THE CONNECTION TO THE 290 00:13:32,371 --> 00:13:33,439 LYMPHATICS. 291 00:13:33,439 --> 00:13:35,841 AND THOUGH IN THE INITIAL STUDY 292 00:13:35,841 --> 00:13:37,276 OUR NUMBERS FOR THE SYNDROMES 293 00:13:37,276 --> 00:13:40,045 WAS NOT HUGE THESE ARE PATTERNS 294 00:13:40,045 --> 00:13:42,448 WE'VE SEEN RECAPITULATED AND 295 00:13:42,448 --> 00:13:44,883 ADDITIONAL PATIENTS IMAGED SINCE 296 00:13:44,883 --> 00:13:48,620 THIS STUDY. 297 00:13:48,620 --> 00:13:53,726 AND OVER ALL 65% HAVE AN 298 00:13:53,726 --> 00:13:54,626 IDENTIFIABLE GENETIC CAUSE BUT 299 00:13:54,626 --> 00:13:59,431 MANY HASN'T HAD TESTING THAT CAN 300 00:13:59,431 --> 00:14:01,400 ADDRESS SOMATIC MOSAICISM. 301 00:14:01,400 --> 00:14:04,269 THAT'S WHEN WE THINK OF HAVING A 302 00:14:04,269 --> 00:14:05,170 DIFFERENT GENETIC PROFILE IN 303 00:14:05,170 --> 00:14:07,873 DIFFERENT AREAS OF OUR BODY. 304 00:14:07,873 --> 00:14:08,474 WHICH IS REPRESENTED BY BLUE 305 00:14:08,474 --> 00:14:10,042 HERE. 306 00:14:10,042 --> 00:14:13,445 AND SO WHAT WE KNOW FOR VASCULAR 307 00:14:13,445 --> 00:14:15,147 MALFORMING AS IN GENERAL IS MANY 308 00:14:15,147 --> 00:14:16,148 FUNCTION LIKE TUMORS OR CANCER 309 00:14:16,148 --> 00:14:17,750 IN THE SENSE THEY HAVE A 310 00:14:17,750 --> 00:14:18,550 DIFFERENT GENETIC PROFILE THAN 311 00:14:18,550 --> 00:14:23,989 THE REPLAINED -- REMAINDER OF 312 00:14:23,989 --> 00:14:25,290 THE BODY REPRESENTED BY BLUE 313 00:14:25,290 --> 00:14:26,058 CELLS HERE. 314 00:14:26,058 --> 00:14:27,326 TYPICALLY IF YOU WANT TO 315 00:14:27,326 --> 00:14:28,794 IDENTIFY A GENETIC CAUSE YOU 316 00:14:28,794 --> 00:14:30,195 HAVE TO SAMPLE THE BLUE CELLS 317 00:14:30,195 --> 00:14:32,564 NOT JUST THE WHOLE BODY OR AREA 318 00:14:32,564 --> 00:14:34,566 OF UNAFFECTED TISSUE. 319 00:14:34,566 --> 00:14:39,905 SO TYPICALLY BLOOD SAMPLING OR 320 00:14:39,905 --> 00:14:42,041 SALIVA SAMPLING ONE MIGHT DO 321 00:14:42,041 --> 00:14:42,775 WON'T WORK. 322 00:14:42,775 --> 00:14:44,410 WHEN PATIENT HAVE MALFORMATIONS 323 00:14:44,410 --> 00:14:48,614 ON DIFFERENT AREAS OF THE BODY 324 00:14:48,614 --> 00:14:49,948 TYPICALLY WE CAN TAKE A 325 00:14:49,948 --> 00:14:51,450 BYPRODUCT BUT CENTRAL LYMPHATICS 326 00:14:51,450 --> 00:14:55,554 IT CAN BE HARD TO ACCESS AND IT 327 00:14:55,554 --> 00:14:58,023 CAN EXACERBATE DISEASE IN THIS 328 00:14:58,023 --> 00:14:58,323 POPULATION. 329 00:14:58,323 --> 00:15:01,560 WE TURNED TO NUCLEIC ACIDS. 330 00:15:01,560 --> 00:15:02,928 TYPICALLY WHEN WE DO GENETIC 331 00:15:02,928 --> 00:15:04,763 TESTING WE'RE SAMPLING THE DNA 332 00:15:04,763 --> 00:15:06,031 INSIDE CELLS REPRESENTED HERE IN 333 00:15:06,031 --> 00:15:14,039 BLUE. 334 00:15:14,039 --> 00:15:15,207 WE KNOW THERE'S FLUID FOR 335 00:15:15,207 --> 00:15:18,043 EXAMPLE CELL FREE DNA. 336 00:15:18,043 --> 00:15:23,482 SO WHAT WE DID IS USED DISCARDED 337 00:15:23,482 --> 00:15:25,551 FLUID BEING DRAINED AS PART OF 338 00:15:25,551 --> 00:15:26,151 ANY CLINICAL PROCEDURE FOR 339 00:15:26,151 --> 00:15:28,687 GENETIC TESTING. 340 00:15:28,687 --> 00:15:31,557 ESSENTIALLY WE CENTRIFUGED THIS 341 00:15:31,557 --> 00:15:37,563 AND ISOLATED CELL-FREE DNA AND 342 00:15:37,563 --> 00:15:48,107 THEN SEQUENCED THE MALFORMATION 343 00:15:49,608 --> 00:15:59,685 PANELS. 344 00:16:00,519 --> 00:16:01,553 WE WERE ABLE TO EVALUATE THE 345 00:16:01,553 --> 00:16:05,424 GENETIC CAUSES IN COHORTS WITH 346 00:16:05,424 --> 00:16:08,560 VASCULAR ANOMALIES. 347 00:16:08,560 --> 00:16:16,201 WE WERE ABLE TO IDENTIFY AND 348 00:16:16,201 --> 00:16:17,569 THERE WERE GENETIC CHANGES GERM 349 00:16:17,569 --> 00:16:21,940 LINED MEANING THE WHOLE BODY OR 350 00:16:21,940 --> 00:16:25,444 MOS 351 00:16:25,444 --> 00:16:25,677 MOSAIC. 352 00:16:25,677 --> 00:16:26,912 AND SO WHEN WE LOOKED 353 00:16:26,912 --> 00:16:29,781 SPECIFICALLY AT THE PATIENT I 354 00:16:29,781 --> 00:16:30,482 TALKED TO YOU ABOUT BEFORE IN 355 00:16:30,482 --> 00:16:32,751 THE FIRST STUDY WHAT WE SAW 356 00:16:32,751 --> 00:16:35,020 COMPARISON IN THE PROSPECTIVE 357 00:16:35,020 --> 00:16:37,422 STUDY WE WERE ABLE TO IDENTIFY A 358 00:16:37,422 --> 00:16:39,258 GENETIC CAUSE IN 41% OF THOSE 359 00:16:39,258 --> 00:16:39,658 PATIENTS. 360 00:16:39,658 --> 00:16:40,692 I THINK ONE OF THE INTERESTING 361 00:16:40,692 --> 00:16:45,898 THINGS ABOUT THE STUDY IS WE 362 00:16:45,898 --> 00:16:47,566 WERE ABLE TO EXPAND THE GENETIC 363 00:16:47,566 --> 00:16:48,233 CAUSES IN THE THREE DIFFERENT 364 00:16:48,233 --> 00:16:52,437 TYPES OF LYMPHATIC ANOMALIES. 365 00:16:52,437 --> 00:16:54,940 ONE THING WE KNEW OR THOUGHT WE 366 00:16:54,940 --> 00:16:57,042 KNEW IS WE THOUGHT THERE WERE 367 00:16:57,042 --> 00:17:00,179 DISTINCT GENOTYPE AND PHENOTYPE 368 00:17:00,179 --> 00:17:05,117 CORRELATIONS SO THAT FOR EXAMPLE 369 00:17:05,117 --> 00:17:10,322 YOU HAD GENERALIZED MODALITY AND 370 00:17:10,322 --> 00:17:20,799 IN M RAV YOU HAD KAPOSIFORM 371 00:17:25,771 --> 00:17:35,914 CONDITIONS. 372 00:17:37,482 --> 00:17:42,788 WE SAW K RAS IN ALL OF THESE. 373 00:17:42,788 --> 00:17:45,224 SO TO LOOK AT DEFINING DISEASE 374 00:17:45,224 --> 00:17:46,858 FURTHER AT THE NIH CLINICAL 375 00:17:46,858 --> 00:17:49,094 CENTER I ESTABLISHED A 376 00:17:49,094 --> 00:17:50,562 LONGITUDINAL NATURAL HISTORY 377 00:17:50,562 --> 00:17:53,732 STUDY FOR PATIENTS OF LYMPHATIC 378 00:17:53,732 --> 00:17:55,367 ANOMALIES AND ENROLLED 35 379 00:17:55,367 --> 00:17:56,568 PARTICIPANTS TO DATE AND THIS IS 380 00:17:56,568 --> 00:17:59,538 THE WORK OF A HUGE TEAM AND 381 00:17:59,538 --> 00:18:00,505 THAT'S ALLOWING US TO LOOK AT 382 00:18:00,505 --> 00:18:04,343 THE PHENOTYPES GENOTYPES AND 383 00:18:04,343 --> 00:18:06,979 INTERACTIONS OF FLOW IN THE 384 00:18:06,979 --> 00:18:10,382 PATIENT POPULATION. 385 00:18:10,382 --> 00:18:13,652 1:THIS COULD NOT BE DONE WITHOUT 386 00:18:13,652 --> 00:18:14,453 OUR COLLABORATORS AS WELL. 387 00:18:14,453 --> 00:18:17,389 TO LOOK AT GENOTYPES OF DISEASE 388 00:18:17,389 --> 00:18:18,590 AT THIS PATIENT POPULATION WE'RE 389 00:18:18,590 --> 00:18:21,226 LOOKING AT MOSAIC CAUSES WHICH 390 00:18:21,226 --> 00:18:26,465 ALLOW US THROUGH A CELL FREE 391 00:18:26,465 --> 00:18:28,066 VASCULAR MALFORMATION PANEL AND 392 00:18:28,066 --> 00:18:29,201 SEQUENCING LOOKING AT GERM LINE 393 00:18:29,201 --> 00:18:31,803 CAUSES IN COLLABORATION WITH THE 394 00:18:31,803 --> 00:18:38,010 FOLKS AT NIAD AND LOOKING AT 395 00:18:38,010 --> 00:18:38,577 METRICS FOR FUTURE CLINICAL 396 00:18:38,577 --> 00:18:48,720 TRIALS. 397 00:18:50,489 --> 00:18:57,696 WE'RE LOOKING AT THIS IN 398 00:18:57,696 --> 00:18:59,931 COLLABORATION AND LOOKING TO 399 00:18:59,931 --> 00:19:01,900 EXPAND OUR PATIENT POPULATION TO 400 00:19:01,900 --> 00:19:03,535 SPANISH AND WE MEASURE THE 401 00:19:03,535 --> 00:19:05,337 IMPACT OF LYMPHATIC DISEASE IN 402 00:19:05,337 --> 00:19:09,474 BOTH THE PHYSICAL AND EMOTIONAL 403 00:19:09,474 --> 00:19:10,475 WELL BEING OF PATIENTS. 404 00:19:10,475 --> 00:19:15,447 WE'RE ALSO LOOKING AT BIOMARKERS 405 00:19:15,447 --> 00:19:19,685 IN LYMPHATIC FLUID, BLOOD AND 406 00:19:19,685 --> 00:19:24,856 URINE AND IT'S LED BY A 407 00:19:24,856 --> 00:19:27,492 POSTDOCTORAL FELLOW IN MY LAB. 408 00:19:27,492 --> 00:19:31,697 TO SUMMARIZE WE APPLIED 409 00:19:31,697 --> 00:19:34,599 APPROACHES INCLUDING CELL FREE 410 00:19:34,599 --> 00:19:37,703 DNA FOR THE GENETIC TESTING AND 411 00:19:37,703 --> 00:19:41,306 ALLOWED US TO DISCOVER 22 CAUSES 412 00:19:41,306 --> 00:19:46,044 FOR PATIENTS WITH LYMPHATIC 413 00:19:46,044 --> 00:19:46,745 ANORMA 414 00:19:46,745 --> 00:19:49,581 ANOMALIES AND WE FURTHER 415 00:19:49,581 --> 00:19:50,582 DELINEATED THE DISEASES AND TAKE 416 00:19:50,582 --> 00:19:52,718 WHAT WE LEARNED IN THE NATURAL 417 00:19:52,718 --> 00:19:55,887 HISTORY STUDY AND HELP US 418 00:19:55,887 --> 00:19:58,323 UNDERSTAND THE MOLECULAR 419 00:19:58,323 --> 00:19:59,958 PATHOGENESIS OF DISEASE USING 420 00:19:59,958 --> 00:20:01,693 PRECLINICAL MODELS AND USE THE 421 00:20:01,693 --> 00:20:07,799 MODELS TO DEVELOP THERAPEUTICS. 422 00:20:07,799 --> 00:20:12,003 SO K RAS IS TYPICALLY SIGNALS 423 00:20:12,003 --> 00:20:15,507 THROUGH THE RAS KINASE PATHWAY 424 00:20:15,507 --> 00:20:17,442 AND HAS CROSS TALK WITH THE 425 00:20:17,442 --> 00:20:18,143 SIGNALLING PATHWAY. 426 00:20:18,143 --> 00:20:20,479 WE REALLY PURSUED THIS AS A GENE 427 00:20:20,479 --> 00:20:22,814 IN MY LAB TO STUDY BECAUSE WE 428 00:20:22,814 --> 00:20:24,750 KNOW IT'S ONE OF THE MOST COMMON 429 00:20:24,750 --> 00:20:26,518 CAUSES FOR COMPLEX LYMPHATIC 430 00:20:26,518 --> 00:20:26,852 ANOMALIES. 431 00:20:26,852 --> 00:20:28,120 SEE THE NUMBER OF PARTICIPANTS 432 00:20:28,120 --> 00:20:30,021 IN OUR STUDY. 433 00:20:30,021 --> 00:20:32,591 ON THE Y AXIS BY GENE. 434 00:20:32,591 --> 00:20:35,761 ON THE X AXIS WE SEE K RAS IS 435 00:20:35,761 --> 00:20:39,331 REALLY THE SECOND MOST COMMON 436 00:20:39,331 --> 00:20:41,166 CAUSE SHORTLY BEHIND K3CA. 437 00:20:41,166 --> 00:20:43,702 WE ALSO KNOW FROM OUR CLINICAL 438 00:20:43,702 --> 00:20:46,872 EXPERIENCE K RAS IS AN 439 00:20:46,872 --> 00:20:49,741 AGGRESSIVE PATIENTS -- THESE 440 00:20:49,741 --> 00:20:51,343 PATIENTS TEND TO HAVE MORE 441 00:20:51,343 --> 00:20:53,211 AGGRESSIVE DISEASE. 442 00:20:53,211 --> 00:20:54,746 AND SO WHAT WE DID WAS EVALUATE 443 00:20:54,746 --> 00:20:58,049 THE PHENOTYPE IN PATIENTS WITH 444 00:20:58,049 --> 00:21:03,722 CENTRAL CONDUCTING ANOMALY AND 445 00:21:03,722 --> 00:21:05,424 EMPHA DEMA AND THERE WAS A 446 00:21:05,424 --> 00:21:07,993 PHOTOGRAPH OF FOUR PATIENTS WITH 447 00:21:07,993 --> 00:21:09,494 DIFFERENT MOSAIC VARIANTS. 448 00:21:09,494 --> 00:21:12,831 YOU CAN SEE THE VARIANT ALLELE 449 00:21:12,831 --> 00:21:14,132 FRACTION BETWEEN 3% IN THE 450 00:21:14,132 --> 00:21:19,704 AFFECTED TISSUE UP TO 38% AND 451 00:21:19,704 --> 00:21:22,874 THESE WERE DIFFERENT VARIOUS 452 00:21:22,874 --> 00:21:24,576 SAMPLES INCLUDING LYMPHATIC 453 00:21:24,576 --> 00:21:25,710 MALFORMATION, SKIN AND BONE. 454 00:21:25,710 --> 00:21:29,481 THEY ALL HAVE DIFFERENT AREAS OF 455 00:21:29,481 --> 00:21:30,916 CENTRAL LYMPHATIC PROFUSION AND 456 00:21:30,916 --> 00:21:33,885 BACK FLOW IN THE SPLEEN HERE AND 457 00:21:33,885 --> 00:21:38,023 HERE BACKFLOW IN THE PENIS AND 458 00:21:38,023 --> 00:21:38,924 SCROTUM. 459 00:21:38,924 --> 00:21:39,958 REALLY INTERESTINGLY WE ALSO 460 00:21:39,958 --> 00:21:42,527 FOUND THAT PART OF THE LYMPHATIC 461 00:21:42,527 --> 00:21:47,399 PHENOTYPE IN THE K RAS RELATED 462 00:21:47,399 --> 00:21:49,768 ANOMALIES INCLUDED THIS 463 00:21:49,768 --> 00:21:53,638 MALFORMATION STAINED AND YOU AND 464 00:21:53,638 --> 00:22:00,278 YOU CAN SEE THE DILATED VASCULAR 465 00:22:00,278 --> 00:22:05,417 SPACES AND IT'S HIGHLIGHTED BY A 466 00:22:05,417 --> 00:22:06,618 LYMPHATIC ENDOTHELIAL CELL 467 00:22:06,618 --> 00:22:07,152 MARKER. 468 00:22:07,152 --> 00:22:08,186 WE WANTED TO UNDERSTAND WHAT IS 469 00:22:08,186 --> 00:22:09,588 GOING TO BE THE BEST TARGETED 470 00:22:09,588 --> 00:22:11,656 THERAPY FOR THESE PATIENTS. 471 00:22:11,656 --> 00:22:15,927 SO DR. DENISE ADAMS HAS REALLY 472 00:22:15,927 --> 00:22:18,430 ESTABLISHED THE FIELD BIS THE 473 00:22:18,430 --> 00:22:19,197 PIVOTAL STUDY WHERE SHE LOOKED 474 00:22:19,197 --> 00:22:28,607 AT THE EFFICACY AND SAFETY OF 475 00:22:28,607 --> 00:22:30,041 RAPAMYCIN AND OVER ALL MANY 476 00:22:30,041 --> 00:22:31,610 PATIENTS HAD AN IMPROVED 477 00:22:31,610 --> 00:22:32,978 RESPONSE THAT WHEN WE THINK 478 00:22:32,978 --> 00:22:36,314 ABOUT PATIENTS WITH CENTRAL 479 00:22:36,314 --> 00:22:38,817 CONDUCTING ANOMALY THERE WERE 480 00:22:38,817 --> 00:22:42,053 THREE PATIENTS AND THEY ALL HAD 481 00:22:42,053 --> 00:22:43,488 PROGRESS DISEASE EVEN ON THERAPY 482 00:22:43,488 --> 00:22:45,657 THEIR DISEASE WORSENED. 483 00:22:45,657 --> 00:22:47,659 SO WE HYPOTHESIZED IN THE K RAS 484 00:22:47,659 --> 00:22:49,561 PATIENTS BASED ON WHAT WE KNEW 485 00:22:49,561 --> 00:22:52,797 BASED ON OTHER STUDIES THAT WERE 486 00:22:52,797 --> 00:22:59,004 GOING ON AT CHOC THAT MEK 487 00:22:59,004 --> 00:23:04,209 INHIBITORS MAY BE MORE 488 00:23:04,209 --> 00:23:05,176 EFFICACIOUS AND WE USED THE 489 00:23:05,176 --> 00:23:06,778 ZEBRAFISH AND THE GENETICS ARE 490 00:23:06,778 --> 00:23:09,614 WELL CONSERVED WITH HUMANS AND 491 00:23:09,614 --> 00:23:10,615 WE HAVE THESE UNIQUE 492 00:23:10,615 --> 00:23:13,485 CAPABILITIES FOR US TO IMAGE AND 493 00:23:13,485 --> 00:23:17,322 ALSO EVALUATE THE VASCULATURE. 494 00:23:17,322 --> 00:23:21,092 SO WE HAVE THESE TRANS GENETIC 495 00:23:21,092 --> 00:23:22,027 ZEBRAFISH WHERE THEY SCAN 496 00:23:22,027 --> 00:23:25,430 EXPRESS THE PROTEINS IN THE 497 00:23:25,430 --> 00:23:28,133 LYMPHATIC AND BONE VASCULATURE 498 00:23:28,133 --> 00:23:29,000 AND BECAUSE THEY DEVELOP RAPIDLY 499 00:23:29,000 --> 00:23:31,403 AND EXTERNALLY FROM THE MOTHER 500 00:23:31,403 --> 00:23:34,372 WE CAN SEE HOW THE VASCULATURE 501 00:23:34,372 --> 00:23:35,907 DEVELOPS OR MAYBE DEVELOPS 502 00:23:35,907 --> 00:23:37,776 ABNORMALLY WHEN WE INTRODUCE 503 00:23:37,776 --> 00:23:40,779 DIFFERENT GENETIC CHANGES WHICH 504 00:23:40,779 --> 00:23:46,051 ARE PRETTY EASY FOR US TO DO IN 505 00:23:46,051 --> 00:23:49,087 THE ZEBRAFISH AND ONE ADULT 506 00:23:49,087 --> 00:23:53,124 FEMALE MAY HAVE 200 TO 300 EGGS 507 00:23:53,124 --> 00:23:55,760 AND CAN FACILITATE DRUG 508 00:23:55,760 --> 00:23:57,529 SCREENING. 509 00:23:57,529 --> 00:23:59,531 WE CREATED A ZEBRAFISH MODEL 510 00:23:59,531 --> 00:24:02,601 USING AN MRC1A PROMOTER TO DRIVE 511 00:24:02,601 --> 00:24:03,501 EXPRESSION OF WILD TYPE K RAS AS 512 00:24:03,501 --> 00:24:08,974 A CONTROL OR ONE OF THE PATIENT 513 00:24:08,974 --> 00:24:12,844 ALLELES IN THE ZEBRAFISH 514 00:24:12,844 --> 00:24:13,144 ENDOTHELIUM. 515 00:24:13,144 --> 00:24:14,045 HERE'S IMAGES OF THE ZEBRAFISH 516 00:24:14,045 --> 00:24:16,081 IN THE CONTROL. 517 00:24:16,081 --> 00:24:17,549 THEY'RE HEALTHY AND THE VESSELS 518 00:24:17,549 --> 00:24:20,719 LOOK NICE AND THIN AND ARE NOT 519 00:24:20,719 --> 00:24:24,723 DILATED AND IN THE PATIENT 520 00:24:24,723 --> 00:24:27,292 ZEBRAFISH THERE'S EDEMA AND 521 00:24:27,292 --> 00:24:31,663 INTESTINAL EDEMA AND SEE THE 522 00:24:31,663 --> 00:24:42,207 VESSELS LOOK QUITE DIALATE AND 523 00:24:42,941 --> 00:24:44,109 WHEN YOU CREATE THE MOLT IT'S 524 00:24:44,109 --> 00:24:46,578 IMPORTANT TO VALIDATE WHAT YOU 525 00:24:46,578 --> 00:24:52,917 SEE HAPPENING MEC MOLECULARLY 526 00:24:52,917 --> 00:24:54,285 AND WE TOOK THE ZEBRAFISH MODELS 527 00:24:54,285 --> 00:24:58,023 AND SUBJECT THEM AT FIVE DAYS TO 528 00:24:58,023 --> 00:24:59,557 RNA SEQUENCING. 529 00:24:59,557 --> 00:25:04,696 THIS IS A RADAR PLOT AND OUTSIDE 530 00:25:04,696 --> 00:25:07,165 YOU SEE THE TERMS AND IN ORANGE 531 00:25:07,165 --> 00:25:10,035 HOW UP REGULATED THAT IS IN THE 532 00:25:10,035 --> 00:25:13,371 MODEL COMPARED TO THE CONTROL. 533 00:25:13,371 --> 00:25:16,775 AS WE COULD EXPECT WE SEE THIS 534 00:25:16,775 --> 00:25:19,778 UP REGULATION OF GENES AND 535 00:25:19,778 --> 00:25:22,647 TRANSCRIPTS ASSOCIATED WITH 536 00:25:22,647 --> 00:25:25,784 TRANSDUCTION IN SMALL GTPAs AND 537 00:25:25,784 --> 00:25:29,654 ASSOCIATIONS WITH ANGIOGENESIS 538 00:25:29,654 --> 00:25:32,390 AND ENDOTHELIAL CELL MIGRATION 539 00:25:32,390 --> 00:25:35,326 SO IN THE ZEBRAFISH WE WANTED TO 540 00:25:35,326 --> 00:25:37,362 UNDERSTAND WHAT DRUGS WERE 541 00:25:37,362 --> 00:25:37,762 EFFICACIOUS. 542 00:25:37,762 --> 00:25:40,031 TO DO THIS WE USE OUR MODEL AND 543 00:25:40,031 --> 00:25:42,901 THEN TREAT THEM WITH DRUGS FROM 544 00:25:42,901 --> 00:25:45,704 TWO DAYS TO FIVE DAYS OLD AND 545 00:25:45,704 --> 00:25:47,872 THEN WE CAN IMAGE THE ZEBRAFISH 546 00:25:47,872 --> 00:25:48,840 AND ESSENTIALLY CAN SCREEN FOR 547 00:25:48,840 --> 00:25:50,608 THIS EDEMA AS A METRIC OF HOW 548 00:25:50,608 --> 00:25:53,578 WELL THE DRUG IS WORKING. 549 00:25:53,578 --> 00:25:57,882 SO FIRST WE LOOKED AT MTOR 550 00:25:57,882 --> 00:26:01,419 INHIBITORS AND ONE USED OFFLABOR 551 00:26:01,419 --> 00:26:07,826 AND OSI 27 AN MTOR INHIBITOR AND 552 00:26:07,826 --> 00:26:09,961 WE SAW KEV DEF 553 00:26:25,243 --> 00:26:35,620 NEXT WE LOOKED AT DIFFERENT MEK 554 00:26:35,620 --> 00:26:37,822 INHIBITORS AND VASCULAR 555 00:26:37,822 --> 00:26:40,925 MALFORMATIONS ARE SUCH A SMALL 556 00:26:40,925 --> 00:26:42,060 PROPORTION OF PATIENTS COMPARED 557 00:26:42,060 --> 00:26:43,128 TO CANCER. 558 00:26:43,128 --> 00:26:44,629 YOU CAN IMAGINE IF A COMPANY CAN 559 00:26:44,629 --> 00:26:45,930 MAKE A LOT OF MONEY FROM A 560 00:26:45,930 --> 00:26:48,266 CANCER DRUG THEY PROBABLY DON'T 561 00:26:48,266 --> 00:26:50,769 WANT YOU TO GIVE THEIR DRUG NOT 562 00:26:50,769 --> 00:26:55,840 APPROVED FOR ONE INDICATION TO A 563 00:26:55,840 --> 00:26:59,043 SMALLER INDICATION AND DISCOVER 564 00:26:59,043 --> 00:27:00,845 A SIDE EFFECT. 565 00:27:00,845 --> 00:27:02,747 ONE THERAPEUTIC MAY HAVE A 566 00:27:02,747 --> 00:27:04,048 DIFFERENT AFFECT IN DIFFERENT 567 00:27:04,048 --> 00:27:05,784 CELL TYPES SO IT'S IMPORTANT FOR 568 00:27:05,784 --> 00:27:08,820 US WHEN WE'RE LOOKING AT 569 00:27:08,820 --> 00:27:09,621 LYMPHATIC ENDOTHELIUM TO 570 00:27:09,621 --> 00:27:11,990 UNDERSTAND WHAT MAY WORK BEST. 571 00:27:11,990 --> 00:27:14,292 SO REALLY ALL THE MEK INHIBITORS 572 00:27:14,292 --> 00:27:17,929 WE LOOKED AT TRENDED TOWARDS 573 00:27:17,929 --> 00:27:19,430 REDUCTION IN THE PERCENT OF 574 00:27:19,430 --> 00:27:20,765 LARVAE WITH EDEMA AND WE FOUND 575 00:27:20,765 --> 00:27:25,503 THERE WERE A FEW THAT LED TO A 576 00:27:25,503 --> 00:27:25,970 SIGNIFICANT REDUCTION. 577 00:27:25,970 --> 00:27:29,007 AND WHEN WE LOOKED AT THIS 578 00:27:29,007 --> 00:27:31,109 MOLECULARLY THE MEK INHIBITORS 579 00:27:31,109 --> 00:27:32,377 TO A REDUCTION IN THE 580 00:27:32,377 --> 00:27:34,746 UPREGULATION OF TRANSCRIPTS NOW 581 00:27:34,746 --> 00:27:38,316 YOU CAN SEE IN GREEN ARE THE RNA 582 00:27:38,316 --> 00:27:40,451 SEQUENCING TREATMENT AFTER ONE 583 00:27:40,451 --> 00:27:41,452 OF THE MEK INHIBITORS THAT LED 584 00:27:41,452 --> 00:27:51,896 TO SIGNIFICANT REDUCTION. 585 00:27:55,533 --> 00:27:57,468 AND WHEN WE LOOKED SPECIFICALLY 586 00:27:57,468 --> 00:28:01,239 AT TERMS AND TRANSCRIPTS THAT 587 00:28:01,239 --> 00:28:05,310 ARE ASSOCIATED WITH 588 00:28:05,310 --> 00:28:07,045 LYMPHANGIOGENESIS HIGHLIGHTED 589 00:28:07,045 --> 00:28:17,422 HERE WE SAW AFTER THE 590 00:28:25,263 --> 00:28:26,531 COBIMETINIB AND THESE ARE TESTED 591 00:28:26,531 --> 00:28:29,434 IN HUMANS IN THEIR INITIAL 592 00:28:29,434 --> 00:28:29,667 TRIALS. 593 00:28:29,667 --> 00:28:34,038 SO HERE WE USE A LYMPHATIC 594 00:28:34,038 --> 00:28:37,842 ORGANOID SPROUTING ASSAY AND CAN 595 00:28:37,842 --> 00:28:41,312 USE HUMAN ENDOTHELIUM CELLS AND 596 00:28:41,312 --> 00:28:43,848 USE THEM IN WELLS WITH THE GEL 597 00:28:43,848 --> 00:28:45,016 AND THIS ALLOWS THE CELLS TO 598 00:28:45,016 --> 00:28:47,151 STICK TO THEMSELVES SINCE THEY 599 00:28:47,151 --> 00:28:49,387 CAN'T STICK TO THE BOTTOM OF THE 600 00:28:49,387 --> 00:28:51,389 PLATE AND THEN CAN IMPLANT THEM 601 00:28:51,389 --> 00:28:53,958 AND LOOK AT THE SPROUTING 602 00:28:53,958 --> 00:28:54,993 BEHAVIOR OF THESE STEROIDS. 603 00:28:54,993 --> 00:28:58,029 AND THIS IS AN EXAMPLE OF WHAT 604 00:28:58,029 --> 00:29:06,537 MINE LOOKS LIKE. 605 00:29:06,537 --> 00:29:09,407 HERE ARE IMAGES FROM OUR 606 00:29:09,407 --> 00:29:11,743 CONTROLS TREATED WITH CONTROL 607 00:29:11,743 --> 00:29:14,379 DMSO OR TWO MEK INHIBITORS. 608 00:29:14,379 --> 00:29:15,947 WHAT IS HARD TO COMPLETELY 609 00:29:15,947 --> 00:29:17,048 APPRECIATE BUT IN THE CONTROL 610 00:29:17,048 --> 00:29:19,651 YOU CAN SEE THIS IS THE TYPICAL 611 00:29:19,651 --> 00:29:21,419 SPROUTING BEHAVIOR BUT IN THE 612 00:29:21,419 --> 00:29:22,053 TWO-PATIENT VARIANT IT LOOKS 613 00:29:22,053 --> 00:29:24,122 LIKE THERE MAY BE MORE AND 614 00:29:24,122 --> 00:29:24,489 LONGER SPROUTS. 615 00:29:24,489 --> 00:29:26,858 AND IT LOOKS LIKE IN GENERAL THE 616 00:29:26,858 --> 00:29:30,028 SPROUTING BEHAVIOR IS DECREASED 617 00:29:30,028 --> 00:29:31,796 WITH THE TREATMENT. 618 00:29:31,796 --> 00:29:34,065 SO WHEN WE QUANTIFY THIS WE CAN 619 00:29:34,065 --> 00:29:35,233 LOOK AT IT IN DIFFERENT WAYS ONE 620 00:29:35,233 --> 00:29:37,869 IS LOOKING AT THE CUMULATIVE 621 00:29:37,869 --> 00:29:42,373 LENGTH FOR SPROUD SPROUT AND 622 00:29:42,373 --> 00:29:44,175 SEE THE TWO PATIENT VARIANTS IN 623 00:29:44,175 --> 00:29:45,777 THE GRAY AND DARKER GRAY. 624 00:29:45,777 --> 00:29:48,613 WHAT WE SEE IS THERE'S A 625 00:29:48,613 --> 00:29:51,849 SIGNIFICANT REDUCTION IN THAT 626 00:29:51,849 --> 00:29:53,885 LENGTH AFTER TREATMENT WITH 627 00:29:53,885 --> 00:29:56,154 EITHER THE TWO TREATMENTS. 628 00:29:56,154 --> 00:29:58,623 AND SIMILARLY WHEN WE LOOK AT 629 00:29:58,623 --> 00:30:00,458 THE NUMBER OF SPROUTS PER SPHERE 630 00:30:00,458 --> 00:30:02,293 WE SEE A SIGNIFICANT REDUCTION 631 00:30:02,293 --> 00:30:04,595 FOR BOTH THE PATIENT VARIANTS 632 00:30:04,595 --> 00:30:08,399 WITH BOTH THE MEK INHIBITORS 633 00:30:08,399 --> 00:30:08,900 CHOSEN. 634 00:30:08,900 --> 00:30:14,238 FINALLY WHEN WE LOOK AT THE 635 00:30:14,238 --> 00:30:17,241 SPROUT LINE PER SPEAR WE SEE A 636 00:30:17,241 --> 00:30:19,844 SIGNIFICANT REDUCTION FOR THE 637 00:30:19,844 --> 00:30:20,545 G12D VARIANT. 638 00:30:20,545 --> 00:30:22,380 SO JUST TO SUMMARIZE THIS PART 639 00:30:22,380 --> 00:30:25,783 WE HAD THIS PATIENT COHORT OF 640 00:30:25,783 --> 00:30:27,986 PATIENTS WITH LYMPHATIC 641 00:30:27,986 --> 00:30:30,722 ANOMALIES DUE TO K RAS. 642 00:30:30,722 --> 00:30:34,025 WE USED ZEBRAFISH AND CELL 643 00:30:34,025 --> 00:30:37,328 MODELS TO UNDERSTAND WHAT 644 00:30:37,328 --> 00:30:38,396 EFFICACIOUS THERAPY WOULD BE AND 645 00:30:38,396 --> 00:30:42,100 MEK INHIBITORS WERE MORE 646 00:30:42,100 --> 00:30:46,137 EFFICACIOUS THAN THE MTOR 647 00:30:46,137 --> 00:30:46,437 INHIBITORS. 648 00:30:46,437 --> 00:30:47,939 SO WHY WOULD WE USE THIS IN 649 00:30:47,939 --> 00:30:48,206 PATIENTS? 650 00:30:48,206 --> 00:30:49,574 SO BASED ON THE WORK AND OTHER 651 00:30:49,574 --> 00:30:51,642 WORK THAT WAS BEING DONE BY 652 00:30:51,642 --> 00:30:53,111 OTHER GROUPS, WE THOUGHT ABOUT 653 00:30:53,111 --> 00:30:54,946 TRANSITIONING SOME OF OUR 654 00:30:54,946 --> 00:30:56,114 PATIENTS TO MEK INHIBITERS. 655 00:30:56,114 --> 00:31:00,618 THEY HAD TO HAVE A KNOWN OR 656 00:31:00,618 --> 00:31:01,686 SUSPECTED MOLECULAR CAUSE THAT 657 00:31:01,686 --> 00:31:02,420 INCREASED SIGNALLING AND HAD TO 658 00:31:02,420 --> 00:31:04,922 HAVE A FAILURE OF CONVENTIONAL 659 00:31:04,922 --> 00:31:07,191 THERAPIES AND DIMINISHED STATUS 660 00:31:07,191 --> 00:31:08,192 AND POOR QUALITY OF LIFE. 661 00:31:08,192 --> 00:31:11,362 SO THIS IS ONE OF OUR PATIENTS 662 00:31:11,362 --> 00:31:13,865 WHO IS TREATED OFF LABEL. 663 00:31:13,865 --> 00:31:18,970 HE PRESENTED WITH KYLO THORAX 664 00:31:18,970 --> 00:31:22,040 YOU CAN SEE IN THE MRI HE HAS A 665 00:31:22,040 --> 00:31:24,809 SIGNIFICANT AREA OF FLUID. 666 00:31:24,809 --> 00:31:35,353 HIS THIS IS KAPOSI HEME TOSE IS 667 00:31:37,955 --> 00:31:42,560 AND HAD HIS ON HIS IMAGING. 668 00:31:42,560 --> 00:31:48,366 AS WELL AS AN ELEVATED D DIMER. 669 00:31:48,366 --> 00:31:53,805 HE WAS STARTED ON THIS AND HAS 670 00:31:53,805 --> 00:31:55,339 SOME IMPROVEMENT AND WE 671 00:31:55,339 --> 00:31:56,774 IDENTIFIED THIS HOT SPOT 672 00:31:56,774 --> 00:31:59,877 RECURRING AND RAS VARIANT SEEN 673 00:31:59,877 --> 00:32:10,354 BEFORE IN KAPOSI FORM LYM 674 00:32:14,792 --> 00:32:17,962 YOU CAN SEE WE HAVE A REALLY 675 00:32:17,962 --> 00:32:18,896 SIGNIFICANT IMPROVEMENT IN THE 676 00:32:18,896 --> 00:32:21,399 REDUCTION OF THOSE EFFUSIONS. 677 00:32:21,399 --> 00:32:24,001 HIS D DIMER ALSO DECREASED FROM 678 00:32:24,001 --> 00:32:25,970 37 TO 13 AND WAS REALLY 679 00:32:25,970 --> 00:32:28,039 NORMALIZED BY TWO CYCLES OF 680 00:32:28,039 --> 00:32:31,175 THERAPY AND FINALLY HIS 681 00:32:31,175 --> 00:32:31,976 PULMONARY FUNCTION TEST WERE 682 00:32:31,976 --> 00:32:40,885 IMPROVED AS WELL. 683 00:32:40,885 --> 00:32:42,820 SO IN COLLABORATION WITH 684 00:32:42,820 --> 00:32:44,755 DR. SNYDER AND A RESIDENT AT 685 00:32:44,755 --> 00:32:45,723 GEORGETOWN WE LOOKED AT THE 686 00:32:45,723 --> 00:32:47,825 RESPONSES OF OUR PATIENTS WITH 687 00:32:47,825 --> 00:32:49,894 DIFFERENT TYPES OF VASCULAR 688 00:32:49,894 --> 00:32:52,864 MALFORMATION TREATED BY SINGLE 689 00:32:52,864 --> 00:32:55,867 I.N.D. OR OFF LABEL WITH MEK 690 00:32:55,867 --> 00:33:01,873 INHIBITION TYPICALLY WITH 691 00:33:01,873 --> 00:33:04,675 COBIMETINIB AND A QUARTER OF 692 00:33:04,675 --> 00:33:05,343 THESE HAD COMPLETE RESOLUTION OF 693 00:33:05,343 --> 00:33:14,752 THEIR PRESENTING SYMPTOMS. 694 00:33:14,752 --> 00:33:17,321 AND SOME HAS IMPROVEMENT BUT NOT 695 00:33:17,321 --> 00:33:19,090 COMPLETE RESOLUTION AND FIVE HAD 696 00:33:19,090 --> 00:33:20,825 STABLE DISEASE WHICH OVER ALL WE 697 00:33:20,825 --> 00:33:21,559 CONSIDER TO BE A POSITIVE 698 00:33:21,559 --> 00:33:24,996 RESPONSE BECAUSE WE KNOW MANY OF 699 00:33:24,996 --> 00:33:26,731 THESE DISORDERS ARE PROGRESSIVE. 700 00:33:26,731 --> 00:33:29,200 ONE PATIENT HAD PROGRESSIVE 701 00:33:29,200 --> 00:33:30,768 DISEASE BUT SHE WAS QUITE SICK 702 00:33:30,768 --> 00:33:33,704 AND SO I'M NOT SURE THAT 703 00:33:33,704 --> 00:33:35,506 NECESSARILY REALLY IS DUE TO THE 704 00:33:35,506 --> 00:33:37,875 INHIBITOR OR THE INHIBITOR NOT 705 00:33:37,875 --> 00:33:40,511 WORKING. 706 00:33:40,511 --> 00:33:44,949 AND WHEN WE THINK OVERALL AT HOW 707 00:33:44,949 --> 00:33:46,951 GENOMICS CAN ALTER AND CHANGE 708 00:33:46,951 --> 00:33:47,218 TREATMENT. 709 00:33:47,218 --> 00:33:48,152 WHAT WE FOUND IN THE LARGER 710 00:33:48,152 --> 00:33:49,420 STUDY WHEN WE LOOKED AT PATIENTS 711 00:33:49,420 --> 00:33:54,025 ON MEDICAL THERAPY, WHAT WE 712 00:33:54,025 --> 00:33:58,029 FOUND -- WHAT THE GENOMIC 713 00:33:58,029 --> 00:33:58,796 DIAGNOSIS WAS ABLE TO SUPPORT 714 00:33:58,796 --> 00:34:00,231 FOR MANY PATIENTS LED TO A 715 00:34:00,231 --> 00:34:06,003 CHANGE OR INITIATION IN THERAPY 716 00:34:06,003 --> 00:34:08,105 IN ALMOST TWO-THIRDS THAT WERE 717 00:34:08,105 --> 00:34:09,373 CONSIDERING OR ON MEDICAL 718 00:34:09,373 --> 00:34:09,874 THERAPY. 719 00:34:09,874 --> 00:34:11,676 WHEN WE LOOKED AT THE RESPONSE 720 00:34:11,676 --> 00:34:14,712 METRICS WE FOUND TWO-THIRDS ON 721 00:34:14,712 --> 00:34:16,447 MEDICAL THERAPY ACTUALLY HAD 722 00:34:16,447 --> 00:34:17,582 IMPROVEMENT. 723 00:34:17,582 --> 00:34:19,951 AND SO ALL OF THESE THINGS TAKEN 724 00:34:19,951 --> 00:34:23,321 TOGETHER ARE REALLY EXCITING BUT 725 00:34:23,321 --> 00:34:24,855 THEY ALSO SHOW US THAT OUR 726 00:34:24,855 --> 00:34:25,590 THERAPY IS NOT PERFECT AND WE 727 00:34:25,590 --> 00:34:28,125 NEED TO KEEP LOOKING. 728 00:34:28,125 --> 00:34:31,162 AND SO ONE OF THE QUESTIONS WE 729 00:34:31,162 --> 00:34:34,031 ASKED OURSELVES, DOES THERAPY 730 00:34:34,031 --> 00:34:35,366 RESPONSE ACTUALLY VARY BECAUSE 731 00:34:35,366 --> 00:34:37,902 OF THE MOLECULAR MECHANISMS THAT 732 00:34:37,902 --> 00:34:39,370 MAY BE DRIVING DISEASE? 733 00:34:39,370 --> 00:34:40,738 AGAIN TO ANSWER THE QUESTION 734 00:34:40,738 --> 00:34:42,440 WE'VE BEEN FOCUSES ON K RAS 735 00:34:42,440 --> 00:34:43,908 RELATED ANOMALIES. 736 00:34:43,908 --> 00:34:47,545 SO ONE THING THAT WE KNOW IS 737 00:34:47,545 --> 00:34:50,848 THAT THESE VARIANTS ACTUALLY 738 00:34:50,848 --> 00:34:53,751 IMPAIR THE GTP HYDROLYSIS AND 739 00:34:53,751 --> 00:34:57,688 THE VARIANT LEADS TO RAPID 740 00:34:57,688 --> 00:34:58,856 CYCLING ESSENTIALLY OF THE DOWN 741 00:34:58,856 --> 00:34:59,890 STATES OF K RAS. 742 00:34:59,890 --> 00:35:02,727 AND SO WE WONDERED IF PERHAPS 743 00:35:02,727 --> 00:35:06,030 THESE PATIENTS MAY NEED 744 00:35:06,030 --> 00:35:06,964 DIFFERENT TREATMENTS. 745 00:35:06,964 --> 00:35:10,034 SO TO DO THIS, WE DEVELOPED 746 00:35:10,034 --> 00:35:13,404 NOVEL ZEBRAFISH MODELS FOR THE 747 00:35:13,404 --> 00:35:14,138 DIFFERENT ALLELES SEEN IN THE 748 00:35:14,138 --> 00:35:19,343 PATIENT POPULATION. 749 00:35:19,343 --> 00:35:21,812 HERE'S IMAGES OF THE CONTROL IN 750 00:35:21,812 --> 00:35:26,050 HEALTHY ZEBRAFISH YOU HAVE TO 751 00:35:26,050 --> 00:35:27,685 COMPARE AND THESE DIFFERENT 752 00:35:27,685 --> 00:35:28,286 ZEBRAFISH MODELS. 753 00:35:28,286 --> 00:35:29,654 I REALIZE IT'S A LITTLE BIT HARD 754 00:35:29,654 --> 00:35:35,660 TO SEE ON THE SCREEN BUT WHAT WE 755 00:35:35,660 --> 00:35:39,597 KNOW IS THERE'S PERICARDIAL 756 00:35:39,597 --> 00:35:47,405 EDEMAS AND ACYTIC MALFORM S AND 757 00:35:47,405 --> 00:35:50,241 HERE WE CAN LOOK AT THE 758 00:35:50,241 --> 00:35:52,877 PERCENTAGE OF LARVAE ON THE Y 759 00:35:52,877 --> 00:35:58,015 AXIS AND PHENOTYPE ON THE X AXIS 760 00:35:58,015 --> 00:36:02,253 HERE WE SEE A SIGNIFICANT 761 00:36:02,253 --> 00:36:04,822 INCREASE OR THE MALFORMATIONS 762 00:36:04,822 --> 00:36:06,424 COMPARED TO THE CONTROL IN ALL 763 00:36:06,424 --> 00:36:07,024 THREE OF THE PATIENT-BASED 764 00:36:07,024 --> 00:36:11,629 MODELS. 765 00:36:11,629 --> 00:36:13,564 WE ALSO LOOKED AT THE 766 00:36:13,564 --> 00:36:13,864 VASCULATURE. 767 00:36:13,864 --> 00:36:19,136 HERE WE HAVE FOUR IMAGES OF THE 768 00:36:19,136 --> 00:36:22,006 VASCULATURE AND QUANTIFIED THE 769 00:36:22,006 --> 00:36:24,709 FACIAL LYMPHATIC IN THE THREE 770 00:36:24,709 --> 00:36:24,942 MODELS. 771 00:36:24,942 --> 00:36:29,013 SO THE DIAMETER IS HERE ON THE Y 772 00:36:29,013 --> 00:36:30,915 AXIS AND THE DIFFERENT MODELS 773 00:36:30,915 --> 00:36:33,084 ARE HERE ON THE X AXIS AND WHAT 774 00:36:33,084 --> 00:36:36,620 WE SAW IS THERE IS A SIGNIFICANT 775 00:36:36,620 --> 00:36:38,956 INCREASE IN THE DIAMETER OF THE 776 00:36:38,956 --> 00:36:42,059 LATERAL FACIAL LYMPHATIC 777 00:36:42,059 --> 00:36:43,294 COMPARED TO THE CONTROLS. 778 00:36:43,294 --> 00:36:47,598 WE ALSO WANTED TO LOOK AT THE 779 00:36:47,598 --> 00:36:49,033 THORACIC DUCT AND THE VESSEL IN 780 00:36:49,033 --> 00:36:50,167 THE ZEBRAFISH SIMILAR TO THE 781 00:36:50,167 --> 00:36:50,368 HUMAN. 782 00:36:50,368 --> 00:36:52,636 YOU CAN SEE IN THE MODELS WE CAN 783 00:36:52,636 --> 00:36:55,139 HAVE DILATION, WE CAN HAVE 784 00:36:55,139 --> 00:36:57,508 SEGMENTS AND PUT ALL THESE 785 00:36:57,508 --> 00:37:00,845 TOGETHER TO CHARACTERIZE THEM AS 786 00:37:00,845 --> 00:37:04,014 THORACIC LYMPH DUCT 787 00:37:04,014 --> 00:37:05,950 MALFORMATIONS AND SEE HERE ON 788 00:37:05,950 --> 00:37:07,918 THE Y AXIS. 789 00:37:07,918 --> 00:37:12,223 ALL THREE MODELS ABOUT 75% HAD 790 00:37:12,223 --> 00:37:14,425 THORACIC DUCT MALFORMATIONS A 791 00:37:14,425 --> 00:37:16,460 SIGNIFICANT INCREASE COMPARED TO 792 00:37:16,460 --> 00:37:16,727 CONTROLS. 793 00:37:16,727 --> 00:37:19,063 THEN WE WANTED TO THINK ABOUT 794 00:37:19,063 --> 00:37:20,398 THE MOST EFFICACIOUS THERAPIES 795 00:37:20,398 --> 00:37:23,734 AND TO DO THIS WE'RE USING WHAT 796 00:37:23,734 --> 00:37:25,903 WE IDENTIFIED IN OUR FIRST STUDY 797 00:37:25,903 --> 00:37:28,305 AS CONTROLS. 798 00:37:28,305 --> 00:37:29,740 BECAUSE WE DID NOT TEST THEM IN 799 00:37:29,740 --> 00:37:31,442 ALL THE VARIANTS INITIALLY AND 800 00:37:31,442 --> 00:37:33,677 THEN WE'RE LOOKING AT MORE 801 00:37:33,677 --> 00:37:35,012 DIRECT RAS INHIBITORS. 802 00:37:35,012 --> 00:37:36,714 SO THERE'S BEEN THE DEVELOPMENT 803 00:37:36,714 --> 00:37:40,785 OF THE SMALL MOLECULE AND ALLELE 804 00:37:40,785 --> 00:37:42,586 SPECIFIC INHIBITORS FOR K RAS 805 00:37:42,586 --> 00:37:46,357 FOR THE G12C MUTANT AND THEN 806 00:37:46,357 --> 00:37:48,559 THERE'S BEEN WORK DONE TO 807 00:37:48,559 --> 00:37:50,895 DEVELOP K RAS INHIBITORS. 808 00:37:50,895 --> 00:37:53,097 SO WE'RE USING THE SAME 809 00:37:53,097 --> 00:37:55,466 PROCEDURE WE USED BEFORE WHERE 810 00:37:55,466 --> 00:37:58,035 ESSENTIALLY WE HAVE OUR 811 00:37:58,035 --> 00:37:59,904 ZEBRAFISH MODEL AND SCREENING TO 812 00:37:59,904 --> 00:38:01,906 UNDERSTAND WHETHER OR NOT THE 813 00:38:01,906 --> 00:38:09,914 ZEBRAFISH ARE HEALTHY OR SICK. 814 00:38:09,914 --> 00:38:11,749 FIRST WE USED THE MTOR INHIBITOR 815 00:38:11,749 --> 00:38:13,317 AND YOU'LL SEE THE FRACTION OF 816 00:38:13,317 --> 00:38:17,488 EDEMA OR THE PERCENTAGE HERE ON 817 00:38:17,488 --> 00:38:19,924 THE Y AXIS AND EACH OF THE 818 00:38:19,924 --> 00:38:22,726 MODELS ON THE X AXIS AND MINUS 819 00:38:22,726 --> 00:38:24,929 AND PLUS SIGN REALLY JUST 820 00:38:24,929 --> 00:38:28,065 DELINEATES WHETHER OR NOT THERE 821 00:38:28,065 --> 00:38:33,037 WAS DRUG OR NOT SO WHAT WE SAW 822 00:38:33,037 --> 00:38:37,441 IN THE MODEL IS IT LED TO A 823 00:38:37,441 --> 00:38:40,744 REDUCTION FOR THE A146 ZEBRAFISH 824 00:38:40,744 --> 00:38:43,914 MODEL AS A METRIC OF 825 00:38:43,914 --> 00:38:44,849 IMPROVEMENT. 826 00:38:44,849 --> 00:38:45,549 ANECDOTALLY IT'S SUPER 827 00:38:45,549 --> 00:38:47,451 INTERESTING TO US BECAUSE ONE OF 828 00:38:47,451 --> 00:38:52,823 OUR PATIENTS HAD ACTUALLY 829 00:38:52,823 --> 00:38:53,924 IMPROVE 830 00:38:53,924 --> 00:38:57,328 IMPROVEMENT ON THIS PRIOR TO THE 831 00:38:57,328 --> 00:38:57,695 EMBOLIZATION. 832 00:38:57,695 --> 00:38:58,963 WHEN WE LOOKED AT THE MEK 833 00:38:58,963 --> 00:38:59,930 INHIBITORS WHAT WE FOUND IS 834 00:38:59,930 --> 00:39:02,032 THERE WAS A SIGNIFICANT 835 00:39:02,032 --> 00:39:05,569 REDUCTION IN ALL OF THE 836 00:39:05,569 --> 00:39:08,772 DIFFERENT VARIANTS. 837 00:39:08,772 --> 00:39:12,376 AND THEN WHEN WE LOOKED AT THE K 838 00:39:12,376 --> 00:39:15,779 RAS INHIBITORS VI2493, WE SAW 839 00:39:15,779 --> 00:39:19,350 THAT REALLY THERE WAS A TREND 840 00:39:19,350 --> 00:39:22,820 TOWARDS IMPROVEMENT IN BOTH THE 841 00:39:22,820 --> 00:39:24,288 G12C AND THE G12D MODEL BUT YOU 842 00:39:24,288 --> 00:39:26,023 CAN SEE IN THE EXPERIMENTS THERE 843 00:39:26,023 --> 00:39:28,492 WAS MORE VARIABILITY WHICH MAY 844 00:39:28,492 --> 00:39:31,929 EXPLAIN THE FACT THIS WAS ONLY A 845 00:39:31,929 --> 00:39:34,031 SIGNIFICANT REDUCTION IN THE 846 00:39:34,031 --> 00:39:44,241 A146T MODEL. 847 00:39:45,109 --> 00:39:46,677 AND THE INHIBITERS LED TO A 848 00:39:46,677 --> 00:39:57,221 SIGNIFICANT REDUCTION OF EDEMA. 849 00:39:58,389 --> 00:40:01,926 THEN WE SAW THIS LED TO A 850 00:40:01,926 --> 00:40:06,797 SIGNIFICANT REDUCTION OF EDEMA 851 00:40:06,797 --> 00:40:08,465 IN OUR 12D MODEL. 852 00:40:08,465 --> 00:40:09,867 EXCITINGLY I THINK WE'VE NOW 853 00:40:09,867 --> 00:40:11,802 IDENTIFIED NOVEL INHIBITORS THAT 854 00:40:11,802 --> 00:40:15,673 HAVE SHOWN EFFICACY IN THE 855 00:40:15,673 --> 00:40:18,842 PRECLINICAL ZEBRAFISH MODEL BUT 856 00:40:18,842 --> 00:40:20,144 ARE INTERESTED IN OUR FUTURE 857 00:40:20,144 --> 00:40:22,446 WORK TO UNDERSTAND HOW THE 858 00:40:22,446 --> 00:40:23,881 THERAPIES ARE AFFECTING THE 859 00:40:23,881 --> 00:40:26,717 MALFORMATIONS AND THIS 860 00:40:26,717 --> 00:40:27,518 MECHANISMS DRIVING DISEASE WHICH 861 00:40:27,518 --> 00:40:30,120 HOPEFULLY I'LL GET TO TELL YOU 862 00:40:30,120 --> 00:40:34,325 ABOUT IN FUTURE WORK. 863 00:40:34,325 --> 00:40:37,094 SO TODAY I HAVE TALKED TO YOU A 864 00:40:37,094 --> 00:40:38,128 LITTLE BIT ABOUT THE STEPS MY 865 00:40:38,128 --> 00:40:41,231 GROUP HAS BEEN TAKING TOWARDS 866 00:40:41,231 --> 00:40:41,799 PERSONALIZED MEDICINE FOR 867 00:40:41,799 --> 00:40:42,933 VASCULAR MALFORMATIONS. 868 00:40:42,933 --> 00:40:46,036 THE STEPS WE'RE TAKING TO 869 00:40:46,036 --> 00:40:47,738 IMPROVE DIAGNOSIS THROUGH 870 00:40:47,738 --> 00:40:48,606 GENETIC TESTING INCLUDING SOME 871 00:40:48,606 --> 00:40:50,507 OF THE NOVEL GENETIC CAUSES 872 00:40:50,507 --> 00:40:51,642 WE'VE IDENTIFIED AND THE 873 00:40:51,642 --> 00:40:54,511 DEVELOPMENT OF THE CELL-FREE DNA 874 00:40:54,511 --> 00:40:56,747 TESTING AS WELL AS THE 875 00:40:56,747 --> 00:40:59,216 DEVELOPMENT OF THE NATURAL 876 00:40:59,216 --> 00:41:00,050 HISTORY STUDY. 877 00:41:00,050 --> 00:41:01,919 I SPOKE TO YOU TODAY ABOUT THE 878 00:41:01,919 --> 00:41:04,021 WORK WE'VE DONE ON K RAS RELATED 879 00:41:04,021 --> 00:41:07,257 LYMPHATIC ANOMALIES BUT WE 880 00:41:07,257 --> 00:41:10,027 WORKED ON OTHER LYMPHATIC 881 00:41:10,027 --> 00:41:13,597 ANOMALIES AND THERE'S FOLKS IN 882 00:41:13,597 --> 00:41:14,331 MY LAB AS WELL AS OTHERS THAT 883 00:41:14,331 --> 00:41:17,267 ARE WORKING ON CANDIDATE GENES 884 00:41:17,267 --> 00:41:18,802 FOR THESE LYMPHATIC ANOMALIES 885 00:41:18,802 --> 00:41:20,371 AND THEN FINALLY I SHOWED YOU 886 00:41:20,371 --> 00:41:22,806 HOW SOME OF THESE STUDIES CAN 887 00:41:22,806 --> 00:41:24,742 LEAD US TO IMPROVED TREATMENT 888 00:41:24,742 --> 00:41:27,578 FOR PATIENTS AND WHY WE NEED TO 889 00:41:27,578 --> 00:41:29,980 ACTUALLY LOOK FURTHER TO 890 00:41:29,980 --> 00:41:31,348 CONTINUE IDENTIFYING NOVEL 891 00:41:31,348 --> 00:41:32,249 THERAPIES FOR THESE PATIENT 892 00:41:32,249 --> 00:41:35,152 POPULATION. 893 00:41:35,152 --> 00:41:36,787 SO REALLY THIS BEDSIDE TO BENCH 894 00:41:36,787 --> 00:41:39,523 AND BACK PROGRAM FOR LYMPHATIC 895 00:41:39,523 --> 00:41:42,026 ANOMALIES FUNCTIONS AS AN 896 00:41:42,026 --> 00:41:43,360 ITERATIVE CIRCLE. 897 00:41:43,360 --> 00:41:44,461 SO WE'VE PHENOTYPED AND 898 00:41:44,461 --> 00:41:46,430 GENOTYPED THESE PATIENTS AND 899 00:41:46,430 --> 00:41:49,600 USED THE MODEL TO DEVELOP 900 00:41:49,600 --> 00:41:51,268 THERAPIES AND BROUGHT THESE BACK 901 00:41:51,268 --> 00:41:52,403 TO THE PATIENTS BUT FOUND WE 902 00:41:52,403 --> 00:41:54,304 COULD STILL USE IMPROVEMENT SO 903 00:41:54,304 --> 00:41:55,205 NOW WE'RE GOING BACK TO THE 904 00:41:55,205 --> 00:41:57,441 MODEL TO IDENTIFY MORE WE CAN 905 00:41:57,441 --> 00:41:58,208 HOPEFULLY THEN BRING BACK TO OUR 906 00:41:58,208 --> 00:42:05,215 PATIENT POPULATION. 907 00:42:05,215 --> 00:42:06,884 THOUGH I'VE FOCUSSED ON 908 00:42:06,884 --> 00:42:10,020 LYMPHATIC MALFORMATIONS WE KNOW 909 00:42:10,020 --> 00:42:11,588 OTHER TYPES OF VASCULAR 910 00:42:11,588 --> 00:42:12,322 MALFORMATIONS HAVE GENETIC 911 00:42:12,322 --> 00:42:13,991 CAUSES IN THE SAME PATHWAY AND 912 00:42:13,991 --> 00:42:16,393 KNOW PROBLEMS IN LYMPHATIC 913 00:42:16,393 --> 00:42:18,028 DEVELOPMENT AFFECT OTHER PATIENT 914 00:42:18,028 --> 00:42:20,464 POPULATIONS SUCH AS LYMPHEDEMA 915 00:42:20,464 --> 00:42:22,332 AFTER BREAST CANCER SURGERY AND 916 00:42:22,332 --> 00:42:25,969 KNOW THERE'S DEVELOPMENTAL 917 00:42:25,969 --> 00:42:29,540 DISORDERS FOR OTHER RASOPATHIES 918 00:42:29,540 --> 00:42:31,742 AND WE KNOW THERE'S MANY CANCERS 919 00:42:31,742 --> 00:42:34,011 THAT SHARE SOME OF THESE SAME 920 00:42:34,011 --> 00:42:36,480 GENETIC CHANGES IN SAME GENETIC 921 00:42:36,480 --> 00:42:36,847 DRIVERS. 922 00:42:36,847 --> 00:42:39,883 SO REALLY THE INSIGHTS MY 923 00:42:39,883 --> 00:42:41,485 PROGRAM IS GETTING AT MAY REACH 924 00:42:41,485 --> 00:42:42,419 FURTHER THAN JUST OUR PATIENT 925 00:42:42,419 --> 00:42:52,529 POPULATION. 926 00:42:52,529 --> 00:42:53,630 AND THIS INCLUDES OUR 927 00:42:53,630 --> 00:42:56,533 PARTICIPANTS AND OUR FAMILIES 928 00:42:56,533 --> 00:42:58,902 AND THE INDEX PATIENT'S MOTHER 929 00:42:58,902 --> 00:43:01,371 WHO IS BECOMING AN INCREDIBLE 930 00:43:01,371 --> 00:43:02,306 COLLABORATOR AND MY ENTIRE 931 00:43:02,306 --> 00:43:04,508 RESEARCH GROUP WHO HAS DONE A 932 00:43:04,508 --> 00:43:06,076 PHENOMENAL JOB IN HELPING ME 933 00:43:06,076 --> 00:43:08,045 DEVELOP THE PROGRAM. 934 00:43:08,045 --> 00:43:09,513 ALL THE INCREDIBLE PEOPLE AT 935 00:43:09,513 --> 00:43:12,516 NICHD AND OUR CLINICAL CENTER 936 00:43:12,516 --> 00:43:13,984 COLLABORATORS WHO ALSO WOULD NOT 937 00:43:13,984 --> 00:43:15,853 HAVE BEEN POSSIBLE TO ESTABLISH 938 00:43:15,853 --> 00:43:18,021 ALL THIS WITHOUT THEM. 939 00:43:18,021 --> 00:43:20,758 MY COLLABORATORS AT CHOC 940 00:43:20,758 --> 00:43:23,160 ESPECIALLY DR. SNYDER AND SMITH 941 00:43:23,160 --> 00:43:26,797 WHO IS NOW LEADING A SECONDARY 942 00:43:26,797 --> 00:43:27,865 SITE OF OUR NATURAL HISTORY 943 00:43:27,865 --> 00:43:29,633 STUDY WHICH WE ESTABLISHED NOW 944 00:43:29,633 --> 00:43:31,702 AT CHOC AND OUR PATIENT AND 945 00:43:31,702 --> 00:43:32,636 FAMILY FOUNDATION AND 946 00:43:32,636 --> 00:43:35,172 COLLABORATORS AS WELL WHO 947 00:43:35,172 --> 00:43:36,273 PROVIDE INSIGHT AND FEEDBACK 948 00:43:36,273 --> 00:43:39,409 ABOUT OUR STUDIES. 949 00:43:39,409 --> 00:43:42,112 AND ALL OF THE INCREDIBLE NIH 950 00:43:42,112 --> 00:43:43,981 CLINICAL CENTER COLLABORATORS 951 00:43:43,981 --> 00:43:44,581 HERE. 952 00:43:44,581 --> 00:43:46,383 THANK YOU SO MUCH FOR YOUR 953 00:43:46,383 --> 00:43:47,417 ATTENTION. 954 00:43:47,417 --> 00:43:49,887 I REALIZE I WENT THROUGH THIS 955 00:43:49,887 --> 00:43:50,788 AND SPOKE VERY FAST. 956 00:43:50,788 --> 00:43:51,989 WE HAVE A LOT OF TIME FOR 957 00:43:51,989 --> 00:43:52,256 QUESTIONS. 958 00:43:52,256 --> 00:43:54,057 THANK YOU SO MUCH FOR YOUR 959 00:43:54,057 --> 00:44:01,899 ATTENTION. 960 00:44:01,899 --> 00:44:03,233 >> THANK YOU. 961 00:44:03,233 --> 00:44:04,101 YES, WE HAVE SOME TIME FOR 962 00:44:04,101 --> 00:44:06,904 QUESTIONS SO IF YOU HAVE THEM, 963 00:44:06,904 --> 00:44:07,137 PLEASE. 964 00:44:07,137 --> 00:44:09,973 I'LL START OFF. 965 00:44:09,973 --> 00:44:13,977 SO YOU WERE SHOWING THE PATIENT 966 00:44:13,977 --> 00:44:19,883 S HAVE THESE CENTRAL ANOMALIES 967 00:44:19,883 --> 00:44:23,053 BUT WE DON'T SEEK THAT OUT 968 00:44:23,053 --> 00:44:23,320 OBVIOUSLY. 969 00:44:23,320 --> 00:44:25,088 ONE THING I APPRECIATE IN YOUR 970 00:44:25,088 --> 00:44:27,658 WORK IS SHINING A SPOTLIGHT ON 971 00:44:27,658 --> 00:44:28,859 SOMETHING WE DON'T GIVE MUCH 972 00:44:28,859 --> 00:44:29,927 ATTENTION TO. 973 00:44:29,927 --> 00:44:31,395 SHOULD WE BE PURSUING THIS IN 974 00:44:31,395 --> 00:44:33,130 SOME FASHION? 975 00:44:33,130 --> 00:44:35,232 I DON'T KNOW HOW EASY IT IS TO 976 00:44:35,232 --> 00:44:36,266 DO LYMPHATIC IMAGING. 977 00:44:36,266 --> 00:44:38,101 >> THAT'S A GREAT QUESTION. 978 00:44:38,101 --> 00:44:40,170 NOT EVERYONE HAS LYMPHATIC 979 00:44:40,170 --> 00:44:41,038 IMAGING FIRST OF ALL. 980 00:44:41,038 --> 00:44:42,806 I THINK PEOPLE ONLY HAVE 981 00:44:42,806 --> 00:44:44,641 LYMPHATIC IMAGING IF THEY HAVE A 982 00:44:44,641 --> 00:44:46,510 PROBLEM, FOR EXAMPLE, IF THEY 983 00:44:46,510 --> 00:44:51,248 HAVE EFFUSIONS OR HAVING ACYTIS 984 00:44:51,248 --> 00:44:53,116 AND ONE OF THE THINGS MY 985 00:44:53,116 --> 00:44:54,618 COLLABORATORS IN IMAGES 986 00:44:54,618 --> 00:44:57,020 DR. SMITH AND DR. DORI HAVE DONE 987 00:44:57,020 --> 00:44:58,856 WORK ON IS TRYING TO TEACH OTHER 988 00:44:58,856 --> 00:45:01,992 PEOPLE THE PROCEDURE. 989 00:45:01,992 --> 00:45:07,965 WE ARE SUPER FORTUNATE THAT 990 00:45:07,965 --> 00:45:10,033 RADIOLOGY HELPED US DEVELOP A 991 00:45:10,033 --> 00:45:14,004 PROTOCOL TO IMAGE THE CENTRAL 992 00:45:14,004 --> 00:45:16,807 LYMPHATICS NON-INVASIVELY AS 993 00:45:16,807 --> 00:45:18,542 PART OF OUR SCREENING PROTOCOL 994 00:45:18,542 --> 00:45:24,147 WITH WHOLE BODY MRI BUT NOT ABLE 995 00:45:24,147 --> 00:45:34,691 TO PROVIDE INTERVENTIONS THERE. 996 00:45:36,193 --> 00:45:37,694 IF THEY THINK SOMEONE REQUIRES 997 00:45:37,694 --> 00:45:39,663 IMAGING THEY CAN REFER TO A 998 00:45:39,663 --> 00:45:41,164 LYMPHATIC CENTER IN THE RESEARCH 999 00:45:41,164 --> 00:45:44,301 NETWORK MAINTAINS A LIST OF 1000 00:45:44,301 --> 00:45:45,135 CENTERS OF EXCELLENCE AND 1001 00:45:45,135 --> 00:45:46,236 THERE'S DIFFERENT TIERS 1002 00:45:46,236 --> 00:45:48,138 DEPENDING ON THE NUMBER OF 1003 00:45:48,138 --> 00:45:49,539 SPECIALISTS AND WHAT SERVICES 1004 00:45:49,539 --> 00:45:51,174 ARE PROVIDED AT THE DIFFERENT 1005 00:45:51,174 --> 00:45:52,009 CENTERS AND MAINTAIN THAT FOR 1006 00:45:52,009 --> 00:45:55,946 PLACES ALL AROUND THE WORLD. 1007 00:45:55,946 --> 00:45:59,283 >> AND ANOTHER QUESTION GIVEN 1008 00:45:59,283 --> 00:46:03,053 THE FACT WE DON'T HAVE DIRECTED 1009 00:46:03,053 --> 00:46:06,023 THERAPIES YET IS THERE A ROLE 1010 00:46:06,023 --> 00:46:07,858 FOR OTHER THINGS LIKE DIET. 1011 00:46:07,858 --> 00:46:12,863 I KNOW PATIENTS WHO HAVE 1012 00:46:12,863 --> 00:46:14,398 LYMPHEDEMA ARE THEY AFFECTED? 1013 00:46:14,398 --> 00:46:16,233 >> YEAH, THAT'S ALSO A GREAT 1014 00:46:16,233 --> 00:46:16,934 QUESTION. 1015 00:46:16,934 --> 00:46:18,635 YEAH, DIET IS A HUGE PART 1016 00:46:18,635 --> 00:46:20,938 ESPECIALLY FOR A LOT OF THOSE 1017 00:46:20,938 --> 00:46:26,009 PATIENTS THAT HAVE PRETTY 1018 00:46:26,009 --> 00:46:36,353 SIGNIFICANT PROTEIN LOSING 1019 00:46:36,353 --> 00:46:39,022 OPATHY AND FOR LYMPHEDEMA 1020 00:46:39,022 --> 00:46:40,390 SOMETHING THAT'S IMPORTANT IS 1021 00:46:40,390 --> 00:46:42,426 COMPRESSION AND ARE FORTUNATE TO 1022 00:46:42,426 --> 00:46:45,595 WORK WITH OUR COLLABORATORS 1023 00:46:45,595 --> 00:46:49,333 SEEING OUR PATIENTS BECAUSE AT 1024 00:46:49,333 --> 00:46:50,100 THIS POINT IN TIME COMPRESSION 1025 00:46:50,100 --> 00:46:52,803 IS THE ONE THING WE KNOW HELPS 1026 00:46:52,803 --> 00:46:54,037 PREVENT THE PROGRESSION OF 1027 00:46:54,037 --> 00:47:04,247 LYMPHEDEMA. 1028 00:47:06,083 --> 00:47:09,286 >> IT I'M WONDERING IF YOU SEE 1029 00:47:09,286 --> 00:47:12,522 OTHER MUTATIONS ASSOCIATED WITH 1030 00:47:12,522 --> 00:47:14,024 RAS LIKE RAS ASSOCIATED 1031 00:47:14,024 --> 00:47:15,359 AUTOIMMUNE PROLIFERATIVE 1032 00:47:15,359 --> 00:47:15,926 DISORDER. 1033 00:47:15,926 --> 00:47:17,728 DO THEY GET AUTOIMMUNE 1034 00:47:17,728 --> 00:47:18,362 PHENOMENON AS WELL? 1035 00:47:18,362 --> 00:47:20,297 >> THAT'S A REALLY GOOD 1036 00:47:20,297 --> 00:47:30,474 QUESTION. 1037 00:47:35,679 --> 00:47:37,147 >> IT'S NOT SOMETHING WE 1038 00:47:37,147 --> 00:47:38,915 COMMONLY SEE BUT WE'RE DOING 1039 00:47:38,915 --> 00:47:40,417 DIFFERENT RESEARCH AND DIFFERENT 1040 00:47:40,417 --> 00:47:42,586 PATIENT TO TRULY UNDERSTAND 1041 00:47:42,586 --> 00:47:45,689 WHETHER OR NOT WE ARE SEEING 1042 00:47:45,689 --> 00:47:47,991 THAT PHENOTYPE OVERLAPPING OR 1043 00:47:47,991 --> 00:47:49,960 WHETHER THE PHENOTYPES ARE DUE 1044 00:47:49,960 --> 00:47:53,330 TO OTHER GENETIC DISORDERS. 1045 00:47:53,330 --> 00:47:55,265 >> DO YOU KNOW IF THE SAME 1046 00:47:55,265 --> 00:47:57,167 GENETIC MUTATIONS ARE ASSOCIATED 1047 00:47:57,167 --> 00:48:00,170 WITH DISEASES? 1048 00:48:00,170 --> 00:48:03,306 >> YEAH, NRAS Q61 VARIANT YOU 1049 00:48:03,306 --> 00:48:06,009 SEE IN KRL AND OTHER PROLIF 1050 00:48:06,009 --> 00:48:08,078 PROLIFERATIVE DISEASES. 1051 00:48:08,078 --> 00:48:13,116 >> THANK YOU. 1052 00:48:13,116 --> 00:48:15,118 >> WE HAVE A QUESTION FROM A 1053 00:48:15,118 --> 00:48:16,787 VIEWING EVIDENCE. 1054 00:48:16,787 --> 00:48:19,156 GIVEN THE FDA APPROVED AGENTS 1055 00:48:19,156 --> 00:48:22,292 WITH NO SAFETY PROFILES WHAT DO 1056 00:48:22,292 --> 00:48:24,528 YOU HAVE TO PRIORITIZE FOR OFF 1057 00:48:24,528 --> 00:48:27,364 LABEL USE FOR DISORDERS AND HOW 1058 00:48:27,364 --> 00:48:29,733 DO YOU ENVISION DESIGNING 1059 00:48:29,733 --> 00:48:32,869 PRAGMATIC CLINICAL TRIALS AND 1060 00:48:32,869 --> 00:48:34,671 REGISTRIES FOR EXPANSION OF THE 1061 00:48:34,671 --> 00:48:38,008 THERAPIES FOR THE BROADER 1062 00:48:38,008 --> 00:48:38,942 PATIENT COMMUNITY. 1063 00:48:38,942 --> 00:48:40,610 >> THERE'S A LOT OF QUESTIONS IN 1064 00:48:40,610 --> 00:48:41,011 ONE. 1065 00:48:41,011 --> 00:48:44,981 IN TERMS OF CRITERIA AND PRE 1066 00:48:44,981 --> 00:48:47,050 CLINICAL EVIDENCE, MANY PATIENTS 1067 00:48:47,050 --> 00:48:51,054 HAD FAILED CONVENTIONAL THERAPY 1068 00:48:51,054 --> 00:48:54,758 IN MANY OF THESE EARLY OFF LABEL 1069 00:48:54,758 --> 00:48:54,991 STUDIES. 1070 00:48:54,991 --> 00:48:58,595 SO THINKING ABOUT THINGS WHERE 1071 00:48:58,595 --> 00:49:01,698 PATIENTS ARE NO LONGER 1072 00:49:01,698 --> 00:49:06,002 RESPONDING TO FOR EXAMPLE, 1073 00:49:06,002 --> 00:49:08,371 OTRIOTIDE OR NOT ELIGIBLE FOR 1074 00:49:08,371 --> 00:49:10,006 PROCEDURE SIMILAR TO THE FIRST 1075 00:49:10,006 --> 00:49:14,010 PATIENT I TOLD YOU ABOUT, 1076 00:49:14,010 --> 00:49:20,550 TYPICALLY, MANY ARE OFF LABEL 1077 00:49:20,550 --> 00:49:22,786 DRUG TREATMENT AND HAVE TO BE 1078 00:49:22,786 --> 00:49:25,355 FDA APPROVED THOUGH THERE'S NEW 1079 00:49:25,355 --> 00:49:27,591 TRIALS OPENING UP FOR MEDICINE 1080 00:49:27,591 --> 00:49:31,161 FOR VASCULAR ANOMALY AND THE 1081 00:49:31,161 --> 00:49:32,429 KINASE SPECIFIC INHIBITOR THAT 1082 00:49:32,429 --> 00:49:34,431 IS CURRENTLY THE CLINICAL TRIAL 1083 00:49:34,431 --> 00:49:37,434 IS OPEN FOR COMPLEX LYMPHATIC 1084 00:49:37,434 --> 00:49:38,201 ANOMALIES DEVELOPED BY 1085 00:49:38,201 --> 00:49:38,535 THERAPEUTICS. 1086 00:49:38,535 --> 00:49:40,036 SO PEOPLE ARE STARTING TO THINK 1087 00:49:40,036 --> 00:49:43,840 IN THAT SPACE WHICH IS SUPER 1088 00:49:43,840 --> 00:49:44,107 EXCITING. 1089 00:49:44,107 --> 00:49:45,842 BUT BECAUSE WE'RE NOT A 1090 00:49:45,842 --> 00:49:46,776 THERAPEUTIC COMPANY AT THE NIH 1091 00:49:46,776 --> 00:49:48,044 WE'RE TRYING TO FOCUS ON THINGS 1092 00:49:48,044 --> 00:49:50,380 THAT ARE ALREADY APPROVED FOR 1093 00:49:50,380 --> 00:49:51,882 THINGS OR OTHER DRUGS WHERE WE 1094 00:49:51,882 --> 00:49:55,852 THINK WE MAY LEARN SOMETHING OR 1095 00:49:55,852 --> 00:49:56,753 THEY'RE IN THE APPROVAL PROCESS. 1096 00:49:56,753 --> 00:50:02,025 >> THE SECOND PART OF THE 1097 00:50:02,025 --> 00:50:05,729 QUESTION HOW WOULD YOU ENVISION 1098 00:50:05,729 --> 00:50:07,164 DESIGNING PRAGMATIC TRIALS. 1099 00:50:07,164 --> 00:50:08,932 >> THE THING ABOUT THE COMMUNITY 1100 00:50:08,932 --> 00:50:10,000 IS IT'S SMALL. 1101 00:50:10,000 --> 00:50:10,800 THERE'S WONDERFUL PEOPLE THAT 1102 00:50:10,800 --> 00:50:13,937 COLLABORATE AND I THINK 1103 00:50:13,937 --> 00:50:16,940 DIFFERENT PATIENT GROUPS 1104 00:50:16,940 --> 00:50:19,776 INTERACT WITH RESEARCHERS VERY 1105 00:50:19,776 --> 00:50:19,976 WELL. 1106 00:50:19,976 --> 00:50:22,012 THERE'S A CONSORTIUM OF VASCULAR 1107 00:50:22,012 --> 00:50:24,648 ANOMALIES AND HEMATOLOGISTS 1108 00:50:24,648 --> 00:50:26,016 ONCOLOGISTS CALLED CANVAS WHICH 1109 00:50:26,016 --> 00:50:27,484 IS A GROUP OF THOSE INTERESTED 1110 00:50:27,484 --> 00:50:28,885 IN DRIVING THERAPY FORWARD AND 1111 00:50:28,885 --> 00:50:32,522 SO THAT'S KIND OF A GOOD 1112 00:50:32,522 --> 00:50:34,224 COLLABORATIVE NETWORK THAT MY 1113 00:50:34,224 --> 00:50:38,161 GROUP OR MYSELF I HAVE 1114 00:50:38,161 --> 00:50:43,567 PARTNERSHIPS WITH INCLUDING THE 1115 00:50:43,567 --> 00:50:51,474 PEOPLE IN THE A SPECIAL INTEREST 1116 00:50:51,474 --> 00:50:56,346 GROUP SO I THINK THOSE ARE GOOD 1117 00:50:56,346 --> 00:50:58,882 PEOPLE TO PARTNER WITH FOR 1118 00:50:58,882 --> 00:51:01,117 LEADING CLINICAL TRIALS AND THE 1119 00:51:01,117 --> 00:51:02,586 AMAZING THING IS I FEEL 1120 00:51:02,586 --> 00:51:04,454 FORTUNATE TO CONNECT WITH THE 1121 00:51:04,454 --> 00:51:07,757 PATIENT GROUPS AND I THINK A LOT 1122 00:51:07,757 --> 00:51:09,993 OF THE WORD IS MANY PATIENTS ARE 1123 00:51:09,993 --> 00:51:10,660 CONNECTED THROUGH A LOT OF THESE 1124 00:51:10,660 --> 00:51:13,830 GROUPS AND EVEN STARTING THEIR 1125 00:51:13,830 --> 00:51:20,103 OWN SO WE HAVE TWO PATIENTS THAT 1126 00:51:20,103 --> 00:51:21,805 ARE LONG TERM PATIENTS OF MINE 1127 00:51:21,805 --> 00:51:23,106 BEFORE I CAME HERE AND JOINED 1128 00:51:23,106 --> 00:51:26,643 OUR STUDY AND PARTICIPATED IN 1129 00:51:26,643 --> 00:51:29,379 THIS VIRTUAL SUPPORT GROUP AND 1130 00:51:29,379 --> 00:51:31,248 ONE I DIDN'T HAVE TIME TO TALK 1131 00:51:31,248 --> 00:51:32,849 ABOUT TODAY AND THOUGH THE 1132 00:51:32,849 --> 00:51:34,718 SUPPORT GROUP HAD LOW ENROLLMENT 1133 00:51:34,718 --> 00:51:36,820 WHAT THE TWO PARENTS FOUND WAS 1134 00:51:36,820 --> 00:51:38,021 THAT THEY JUST FELT LIKE IT WAS 1135 00:51:38,021 --> 00:51:41,391 SO HELPFUL TO TALK TO OTHER 1136 00:51:41,391 --> 00:51:43,860 FAMILIES ON A REGULAR BASIS AND 1137 00:51:43,860 --> 00:51:46,463 SO WHAT THEY DID WAS START THEIR 1138 00:51:46,463 --> 00:51:47,631 OWN VIRTUAL SUPPORT GROUPS SO 1139 00:51:47,631 --> 00:51:49,933 THEY CAN ALL COLLABORATE AND 1140 00:51:49,933 --> 00:51:51,334 TALK ABOUT WHAT ARE THE NEW 1141 00:51:51,334 --> 00:51:52,736 INNOVATIONS. 1142 00:51:52,736 --> 00:51:54,304 LAST WE TALKED TO THEM IT WAS 1143 00:51:54,304 --> 00:51:55,605 OVER 90 FAMILIES. 1144 00:51:55,605 --> 00:51:58,441 SO ANYWAY, I GUESS THE SHORT 1145 00:51:58,441 --> 00:52:00,677 ANSWER TO THAT QUESTION IS 1146 00:52:00,677 --> 00:52:02,412 PARTNERING WITH OTHER CLINICIANS 1147 00:52:02,412 --> 00:52:04,881 THROUGH NETWORKS AND DIFFERENT 1148 00:52:04,881 --> 00:52:06,049 ACADEMIC SOCIETIES AS WELL AS 1149 00:52:06,049 --> 00:52:06,983 PARTNERING WITH PATIENTS WITH 1150 00:52:06,983 --> 00:52:09,486 THEIR OWN SUPPORT GROUPS AND THE 1151 00:52:09,486 --> 00:52:11,221 MORE FORMALIZED SUPPORT GROUPS. 1152 00:52:11,221 --> 00:52:13,590 >> I DON'T THINK WE HAVE ANY NOR 1153 00:52:13,590 --> 00:52:14,357 ONLINE QUESTIONS. 1154 00:52:14,357 --> 00:52:18,028 ARE THERE MORE QUESTIONS FROM 1155 00:52:18,028 --> 00:52:21,464 THE AUDIENCE HERE? 1156 00:52:21,464 --> 00:52:23,099 WELL, DR. SHEPPARD, THANK YOU 1157 00:52:23,099 --> 00:52:26,002 VERY MUCH. 1158 00:52:26,002 --> 00:52:26,069