1 00:00:04,760 --> 00:00:09,532 WELL, WELCOME TO ANOTHER 2 00:00:09,532 --> 00:00:11,867 SESSION IN A COURSE IN BRIDGE 3 00:00:11,867 --> 00:00:14,436 BUILDING WHICH IS OFFICIALLY 4 00:00:14,436 --> 00:00:20,776 TERMED DEMIYSTIFYING MEDICINE 5 00:00:20,776 --> 00:00:22,978 HELD AT THE NATIONAL INSTITUTES 6 00:00:22,978 --> 00:00:25,381 OF HEALTH IN BETHESDA, MARYLAND. 7 00:00:25,381 --> 00:00:27,616 WE'RE NOW IN OUR 22nd YEAR AND 8 00:00:27,616 --> 00:00:28,884 MUST BE DOING SOMETHING RIGHT. 9 00:00:28,884 --> 00:00:30,653 THE PURPOSE OF THIS COURSE IS TO 10 00:00:30,653 --> 00:00:33,522 BRIDGE THE EXCITING DEVELOPMENTS 11 00:00:33,522 --> 00:00:35,758 IN BIOLOGY, ENGINEERING AND 12 00:00:35,758 --> 00:00:37,626 COMPUTER SCIENCES WITH MEDICINE 13 00:00:37,626 --> 00:00:41,530 AND WITH HUMAN HEALTH. 14 00:00:41,530 --> 00:00:45,534 IT IS NOT LAST WEEK'S RESEARCH 15 00:00:45,534 --> 00:00:46,869 SEMINAR. 16 00:00:46,869 --> 00:00:48,771 IT IS MORE AN EXERCISE IN BRIDGE 17 00:00:48,771 --> 00:00:55,578 BUILDING AS EXEMPLIFIED BY THE 18 00:00:55,578 --> 00:00:56,779 PHOTOGRAPH IN THE CONSTRUCTION 19 00:00:56,779 --> 00:00:58,113 OF THE BROOKLYN BRIDGE IN WHICH 20 00:00:58,113 --> 00:01:01,016 WE SEE TWO INDIVIDUALS ON THE 21 00:01:01,016 --> 00:01:04,353 CAT WALK OSTENSIBLY REPRESENTING 22 00:01:04,353 --> 00:01:07,022 ENTIRELY DIFFERENT AREAS OF 23 00:01:07,022 --> 00:01:07,656 KNOWLEDGE AND EXPERIENCE AND 24 00:01:07,656 --> 00:01:10,392 SHARING IDEAS. 25 00:01:10,392 --> 00:01:13,162 THE WHOLE CONCEPT IS WILL 26 00:01:13,162 --> 00:01:14,763 BUILDING BRIDGES IN SCIENCE WILL 27 00:01:14,763 --> 00:01:19,568 FACILITATE NEW IDEAS, NEW 28 00:01:19,568 --> 00:01:22,271 APPROACHES AND SHAKE DOWN 29 00:01:22,271 --> 00:01:25,507 SOMETIMES LONG-ACCEPTED 30 00:01:25,507 --> 00:01:26,275 PARADIGMS. 31 00:01:26,275 --> 00:01:28,544 AND TODAY'S PROGRAM IS AN 32 00:01:28,544 --> 00:01:29,878 ELEGANT EXAMPLE OF THAT AND 33 00:01:29,878 --> 00:01:35,517 WE'LL GET TO IN A MOMENT. 34 00:01:35,517 --> 00:01:36,685 SO, DEMYSTIFYING MEDICINE IS 35 00:01:36,685 --> 00:01:40,022 HELD 3:00 TO 5:00 P.M. EASTERN 36 00:01:40,022 --> 00:01:41,390 STANDARD TIME FROM JANUARY 37 00:01:41,390 --> 00:01:42,725 THROUGH THE MONTH OF MAY. 38 00:01:42,725 --> 00:01:46,328 YOU CAN WATCH IT ON THE 39 00:01:46,328 --> 00:01:50,032 VIDEOCAST LINK SHOWN HERE AND AS 40 00:01:50,032 --> 00:01:54,003 PRESENTED A FEW MOMENTS AGO, THE 41 00:01:54,003 --> 00:02:03,045 CME CODE NUMBER IS 58790. 42 00:02:03,045 --> 00:02:04,446 NOW, WE URGE YOU DURING THE TWO 43 00:02:04,446 --> 00:02:05,514 PRESENTATIONS TODAY TO SUBMIT 44 00:02:05,514 --> 00:02:05,981 QUESTIONS. 45 00:02:05,981 --> 00:02:09,518 AND YOU DO THAT BY CLICKING ON 46 00:02:09,518 --> 00:02:11,787 THE SEND LIVE FEEDBACK WHICH IS 47 00:02:11,787 --> 00:02:15,057 ON YOUR VIDEOCAST DISPLAY. 48 00:02:15,057 --> 00:02:18,193 THESE QUESTIONS WILL THEN FORM 49 00:02:18,193 --> 00:02:20,896 THE BASIS OF WHAT IS INVARIABLY 50 00:02:20,896 --> 00:02:24,366 AN EXCITING EXCHANGE OF IDEAS, 51 00:02:24,366 --> 00:02:26,702 INFORMATION WHICH FOLLOWS BOTH 52 00:02:26,702 --> 00:02:28,203 SPEAKERS. 53 00:02:28,203 --> 00:02:29,638 I BRING TO YOUR ATTENTION THAT 54 00:02:29,638 --> 00:02:32,875 ALL PREVIOUS SESSIONS FOR THE 55 00:02:32,875 --> 00:02:36,078 PAST 22 YEARS ARE AVAILABLE 56 00:02:36,078 --> 00:02:38,480 THROUGH THE VIDEOCAST AT NIH. 57 00:02:38,480 --> 00:02:41,517 THE LINK IS SHOWN ON THE SLIDE 58 00:02:41,517 --> 00:02:51,627 HERE. 59 00:02:53,462 --> 00:02:56,098 THERE'S LINK HOW TO CONTACT US. 60 00:02:56,098 --> 00:03:00,736 THE PROGRAM HAS BEEN GOING ON 61 00:03:00,736 --> 00:03:02,237 SINCE 2003 AND DISTRIBUTED 62 00:03:02,237 --> 00:03:04,840 AROUND THE WORLD IN AS MANY AS 63 00:03:04,840 --> 00:03:09,511 38 DIFFERENT COUNTRIES THAT 64 00:03:09,511 --> 00:03:17,019 PARTICIPATE. 65 00:03:17,019 --> 00:03:19,188 SO TODAY'S SUBJECT IS 66 00:03:19,188 --> 00:03:19,888 HEPATOCELLULAR CANCER. 67 00:03:19,888 --> 00:03:21,890 I'D LIKE TO SAY A FEW WORDS 68 00:03:21,890 --> 00:03:23,025 ABOUT IT WHICH MAY SOMETIMES NOT 69 00:03:23,025 --> 00:03:26,862 BE TOO APPARENT TO THOSE 70 00:03:26,862 --> 00:03:28,630 INTERESTED -- NOT INTERESTED 71 00:03:28,630 --> 00:03:31,600 SPECIFICALLY IN THIS FIELD. 72 00:03:31,600 --> 00:03:33,302 APPROXIMATELY 20 YEARS AGO, 73 00:03:33,302 --> 00:03:36,405 MAYBE A LITTLE MORE, IF A 74 00:03:36,405 --> 00:03:38,373 PATIENT IN AN AMERICAN HOSPITAL 75 00:03:38,373 --> 00:03:40,209 HAT HEPATOCELLULAR CANCER THEY 76 00:03:40,209 --> 00:03:41,577 WOULD BE PRESENTED AT GRAND 77 00:03:41,577 --> 00:03:43,579 ROUNDS. 78 00:03:43,579 --> 00:03:49,952 IT WAS THAT UNUSUAL. 79 00:03:49,952 --> 00:03:54,456 WHEREAS IN CHINA AND JAPAN 80 00:03:54,456 --> 00:03:55,390 HEPATOCELLULAR CANCER WAS THE 81 00:03:55,390 --> 00:03:56,658 MAIN REASON FOR PATIENTS BEING 82 00:03:56,658 --> 00:03:57,426 IN THE HOSPITAL. 83 00:03:57,426 --> 00:03:59,528 WHAT CAUSED THIS ENORMOUS 84 00:03:59,528 --> 00:03:59,828 DIFFERENCE? 85 00:03:59,828 --> 00:04:03,065 AND HOW DO WE NOW GET TO THE 86 00:04:03,065 --> 00:04:07,102 POINT WHERE IN THE WORLD 87 00:04:07,102 --> 00:04:08,270 HEPATOCELLULAR CANCER IS ROUGHLY 88 00:04:08,270 --> 00:04:11,874 THE SEVENTH MOST COMMON IN THE 89 00:04:11,874 --> 00:04:17,713 UNITED STATES? 90 00:04:17,713 --> 00:04:19,948 NOW, IT'S USUALLY ASSOCIATED 91 00:04:19,948 --> 00:04:21,884 WITH CHRONIC LIVER DISEASE, 92 00:04:21,884 --> 00:04:25,053 CIRRHOSIS BUT THERE'S OTHER 93 00:04:25,053 --> 00:04:25,954 SITUATIONS. 94 00:04:25,954 --> 00:04:29,458 FOR EXAMPLE, IN YOUNG AFRICAN 95 00:04:29,458 --> 00:04:32,027 MINE WORKERS DEVELOPED A RAPID 96 00:04:32,027 --> 00:04:33,629 ONSET OF HEPATOCELLULAR CANCER. 97 00:04:33,629 --> 00:04:35,731 TODAY WE'LL LEARN ABOUT ANOTHER 98 00:04:35,731 --> 00:04:39,034 FORM WHICH HAS NOT ATTRACTED 99 00:04:39,034 --> 00:04:42,004 MUCH ATTENTION UNTIL THE WORK 100 00:04:42,004 --> 00:04:44,339 PERFORMED BY ONE OF OUR 101 00:04:44,339 --> 00:04:47,276 SPEAKERS, DR. SIMON. 102 00:04:47,276 --> 00:04:51,580 ONE OF THE BIG PROBLEMS THAT 103 00:04:51,580 --> 00:04:54,883 WHILE TRY TO HEAR HOW DO YOU 104 00:04:54,883 --> 00:04:56,618 REGENERATE A NODULE FROM CORNER 105 00:04:56,618 --> 00:04:58,854 OF CANCER AND IS THERE A WAY FOR 106 00:04:58,854 --> 00:04:59,721 SCREENING FOR THIS? 107 00:04:59,721 --> 00:05:01,523 AND IF YOU DO FIND IT, WHAT DO 108 00:05:01,523 --> 00:05:04,993 YOU DO ABOUT IT? 109 00:05:04,993 --> 00:05:08,163 ONE OF THE THINGS I DON'T OFTEN 110 00:05:08,163 --> 00:05:11,300 EMPHASIZE IS LIVER CANCER IS 111 00:05:11,300 --> 00:05:13,435 FOUND IN THE VERY LATE STAGE AND 112 00:05:13,435 --> 00:05:15,838 THAT'S BECAUSE THE PAIN FIBERS 113 00:05:15,838 --> 00:05:17,840 IN THE LIVER ARE NOT PRESENT 114 00:05:17,840 --> 00:05:19,074 EXCEPT ON THE CAPSULE. 115 00:05:19,074 --> 00:05:24,246 AND THERE'S A HUGE FUNCTIONAL 116 00:05:24,246 --> 00:05:25,180 RESERVE. 117 00:05:25,180 --> 00:05:29,518 USUALLY IF A TUMOR IS IN A 118 00:05:29,518 --> 00:05:33,555 STRATEGIC SITE WHERE IT 119 00:05:33,555 --> 00:05:38,393 OBSTRUCTS A MAJOR BLOOD VESSEL 120 00:05:38,393 --> 00:05:41,964 OR CAUSES A CLINICAL DISEASE YOU 121 00:05:41,964 --> 00:05:44,600 SEE IT AS A PHENOMENON BUT MANY 122 00:05:44,600 --> 00:05:46,501 ARE ASYMPTOMATIC FOR LONG PERIOD 123 00:05:46,501 --> 00:05:46,802 OF TIME. 124 00:05:46,802 --> 00:05:57,179 HOW DO WE DETECT THEM? 125 00:06:04,052 --> 00:06:07,656 AND THE TUMOR IS ALMOST DE NOVO, 126 00:06:07,656 --> 00:06:09,858 PATIENTS NOT SUBJECTED TO MANY 127 00:06:09,858 --> 00:06:10,425 CANCER DRUGS. 128 00:06:10,425 --> 00:06:13,428 HOW DOES THAT HAPPEN? 129 00:06:13,428 --> 00:06:16,999 AND ONE OF THE MAJOR STRESSES -- 130 00:06:16,999 --> 00:06:19,968 ONE OF THE MAJOR ASPECTS OF 131 00:06:19,968 --> 00:06:21,136 TODAY'S PRESENTATION IS WHAT CAN 132 00:06:21,136 --> 00:06:25,274 BE LEARNED FROM STUDIES OF RARE 133 00:06:25,274 --> 00:06:28,043 FORMS OF HEPATOCELLULAR CANCER. 134 00:06:28,043 --> 00:06:37,486 AND PARTICULARLY, FIBROLOMELAR 135 00:06:37,486 --> 00:06:37,819 HEPATOCANCER. 136 00:06:37,819 --> 00:06:39,421 OUR TWO SPEAKERS TODAY ARE 137 00:06:39,421 --> 00:06:43,158 DISTINGUISHED IN THIS AREA. 138 00:06:43,158 --> 00:06:45,794 SANFORD SIMON GOT HIS 139 00:06:45,794 --> 00:06:46,695 UNDERGRADUATE DEGREE AT 140 00:06:46,695 --> 00:06:52,134 NEUROSCIENCES AT PRINCETON AND 141 00:06:52,134 --> 00:07:00,809 MASTER'S AND Ph.D. AT NYU AND 142 00:07:00,809 --> 00:07:04,046 WENT TO ROCKEFELLER UNIVERSITY 143 00:07:04,046 --> 00:07:08,016 WORKING WITH GUNTER GLOBEL WHO 144 00:07:08,016 --> 00:07:12,821 IS STILL ONE OF THE LEADING CELL 145 00:07:12,821 --> 00:07:13,455 BIOLOGISTS IN THE FILED. 146 00:07:13,455 --> 00:07:15,023 AMONG HIS CLASSIC STUDIES WAS A 147 00:07:15,023 --> 00:07:17,292 DEMONSTRATION OF A PROTEIN 148 00:07:17,292 --> 00:07:19,594 CONDUCTING CHANNEL IN THE 149 00:07:19,594 --> 00:07:20,529 ENDOPLASM RETICULUM AS PUBLISHED 150 00:07:20,529 --> 00:07:23,198 IN CELL IN 1991. 151 00:07:23,198 --> 00:07:27,970 AND NOW HE'S THE GUNTER BLOBEL 152 00:07:27,970 --> 00:07:31,673 PROFESSOR AT ROCKEFELLER. 153 00:07:31,673 --> 00:07:35,444 AND ABOUT 2013 HIS FOCUS CHANGED 154 00:07:35,444 --> 00:07:38,080 TO CANCER. 155 00:07:38,080 --> 00:07:40,182 AND HE'S PERFORMED A REMARKABLE 156 00:07:40,182 --> 00:07:49,524 SERIES OF STUDIES ON THE RARE 157 00:07:49,524 --> 00:07:51,927 FIBROLOMELAR HEPATAL CANCER. 158 00:07:51,927 --> 00:07:53,562 AND HOW THIS CAME ABOUT WILL BE 159 00:07:53,562 --> 00:07:55,664 PRESENTED IN PART IN HIS 160 00:07:55,664 --> 00:07:58,000 PRESENTATIONS TODAY. 161 00:07:58,000 --> 00:08:01,970 NOW, THROUGHOUT HIS WORK SINCE 162 00:08:01,970 --> 00:08:03,772 2013, THE UNDERLYING THESIS IS 163 00:08:03,772 --> 00:08:08,744 TO FOCUS ON SINGLE EVENTS NOT 164 00:08:08,744 --> 00:08:08,977 GLOBAL. 165 00:08:08,977 --> 00:08:12,147 IN OTHER WORDS, SINGLE PROTEINS, 166 00:08:12,147 --> 00:08:17,352 SINGLE NUCLEAR PORES OR SINGLE 167 00:08:17,352 --> 00:08:21,323 VIRUSES MOLECULES, THAT IS AND 168 00:08:21,323 --> 00:08:24,092 TO PRECISELY IDENTIFY CANCERS TO 169 00:08:24,092 --> 00:08:25,293 IDENTIFY WHAT IS LOST WHEN ONE 170 00:08:25,293 --> 00:08:28,463 AVERAGES ALL THE VARIOUS CHANGES 171 00:08:28,463 --> 00:08:31,033 THAT TAKE PLACE IN A TRANSFORMED 172 00:08:31,033 --> 00:08:33,602 CELL WHICH IS THE USUAL WAY IN 173 00:08:33,602 --> 00:08:37,539 WHICH CANCER STUDIES ARE 174 00:08:37,539 --> 00:08:37,806 PERFORMED. 175 00:08:37,806 --> 00:08:40,609 NOW, AS HE HAS POINTED OUT, THIS 176 00:08:40,609 --> 00:08:42,144 APPROACH ACCELERATES AN 177 00:08:42,144 --> 00:08:43,945 UNDERSTANDING OF MALIGNANT 178 00:08:43,945 --> 00:08:47,315 TRANSFORMATION AND HAS LED TO 179 00:08:47,315 --> 00:08:47,682 CLINICAL TRIALS. 180 00:08:47,682 --> 00:08:50,452 SO SO, HIS CURRENT WORK ON 181 00:08:50,452 --> 00:08:53,555 CHILDHOOD ADOLESCENT AND YOUNG 182 00:08:53,555 --> 00:08:55,724 ADULT CANCERS HAS RUN THE RANGE 183 00:08:55,724 --> 00:08:57,926 THE GAMUT FROM IDENTIFYING 184 00:08:57,926 --> 00:09:01,630 DRIVERS OF MALIGNANT 185 00:09:01,630 --> 00:09:05,567 TRANSFORMATION TO THE DESIGN OF 186 00:09:05,567 --> 00:09:06,001 EFFECTIVE TREATMENT. 187 00:09:06,001 --> 00:09:06,068 188 00:09:07,035 --> 00:09:09,004 THESE ARE MAJOR CHANGES IN THE 189 00:09:09,004 --> 00:09:10,906 PARADIGM OF APPROACH TO CANCER 190 00:09:10,906 --> 00:09:12,207 RESEARCH. 191 00:09:12,207 --> 00:09:14,543 AND WE'RE VERY DELIGHTED THAT 192 00:09:14,543 --> 00:09:16,445 SANDY SIMON HAS BEEN ABLE TO 193 00:09:16,445 --> 00:09:17,345 JOIN US TODAY AND HE WILL BE THE 194 00:09:17,345 --> 00:09:25,687 FIRST SPEAKER. 195 00:09:25,687 --> 00:09:29,257 THE SECOND SPEAKER RECEIVED HIS 196 00:09:29,257 --> 00:09:30,725 MEDICAL DEGREE AT THE ROYAL 197 00:09:30,725 --> 00:09:32,794 COLLEGE OF SURGEONS IN IRELAND 198 00:09:32,794 --> 00:09:35,363 AND MASTER OF HEALTH SCIENCES AT 199 00:09:35,363 --> 00:09:36,031 DUKE UNIVERSITY. 200 00:09:36,031 --> 00:09:38,366 HE TOOK A FELLOWSHIP AT TULANE 201 00:09:38,366 --> 00:09:41,837 WHERE HE WAS ON THE FACULTY AND 202 00:09:41,837 --> 00:09:46,108 CAME TO THE NIH IN 1996. 203 00:09:46,108 --> 00:09:48,810 WHERE HE IS A SENIOR 204 00:09:48,810 --> 00:09:53,548 INVESTIGATOR AND CHIEF OF THE 205 00:09:53,548 --> 00:09:55,450 CLINICAL HEPATOLOGY RESEARCH 206 00:09:55,450 --> 00:09:57,352 SECTION IN THE LIVER DISEASE 207 00:09:57,352 --> 00:09:57,586 BRANCH. 208 00:09:57,586 --> 00:10:01,523 NOW, MARC'S MAJOR FOCUS HAS BEEN 209 00:10:01,523 --> 00:10:05,494 ON CLINICAL STUDIES OF VIRAL 210 00:10:05,494 --> 00:10:07,696 HEPATITIS INCLUDING THEIR 211 00:10:07,696 --> 00:10:10,799 RELATIONSHIP TO HEPATOCELLULAR 212 00:10:10,799 --> 00:10:12,968 CANCER AND RECOGNIZED FOR HIS 213 00:10:12,968 --> 00:10:13,602 EXPERIENCE, KNOWLEDGE, RESEARCH 214 00:10:13,602 --> 00:10:16,571 AND TEACHING ABILITIES. 215 00:10:16,571 --> 00:10:20,142 SO WE'RE VERY GRATEFUL TO YOU 216 00:10:20,142 --> 00:10:22,144 TOO, MARC, FOR TAKING PART IN 217 00:10:22,144 --> 00:10:23,178 TODAY'S PROGRAM. 218 00:10:23,178 --> 00:10:25,547 SO ENOUGH INTRODUCTIONS. 219 00:10:25,547 --> 00:10:35,957 SANDY, PLEASE CONTINUE. 220 00:10:43,031 --> 00:10:45,567 >> THIRST THANK YOU FOR THE 221 00:10:45,567 --> 00:10:47,435 INVITATION TO SPEAK AND 222 00:10:47,435 --> 00:10:48,503 PARTICULARLY THANK YOU FOR YOUR 223 00:10:48,503 --> 00:10:50,272 OPENING INTRODUCTORY SLIDE AS A 224 00:10:50,272 --> 00:10:53,842 BOY WHO GREW UP IN BROOKLYN I 225 00:10:53,842 --> 00:10:54,809 GREATLY APPRECIATE THE PICTURE 226 00:10:54,809 --> 00:10:57,245 OF THE BROOKLYN BRIDGE AND THE 227 00:10:57,245 --> 00:10:58,246 SENTIMENT BEHIND BUILDING 228 00:10:58,246 --> 00:10:59,247 BRIDGES AND REACHING OUT. 229 00:10:59,247 --> 00:11:02,984 TODAY I'LL TELL YOU, AS YOU 230 00:11:02,984 --> 00:11:10,926 HEARD, ABOUT OUR WORK ON FIB 231 00:11:10,926 --> 00:11:21,436 FIBROLAMELLA CARCINOMA AND IF 232 00:11:24,406 --> 00:11:26,007 YOU IDENTIFY THEM YOU CAN MAKE 233 00:11:26,007 --> 00:11:27,209 ADVANCES FOR THAT PARTICULAR 234 00:11:27,209 --> 00:11:28,243 RARE DISEASE AND TAKE HOME 235 00:11:28,243 --> 00:11:29,544 LESSONS TO BE APPLIED TO OTHER 236 00:11:29,544 --> 00:11:39,988 DISEASES AT THE SAME TIME. 237 00:11:41,623 --> 00:11:42,791 THERE'S AN ADVANTAGE IN 238 00:11:42,791 --> 00:11:43,592 PARTNERING WITH THE COMMUNITY 239 00:11:43,592 --> 00:11:45,894 AND IT WAS DESCRIBED AS WHAT YOU 240 00:11:45,894 --> 00:11:47,462 WANT TO BRING IT TO THE KITCHEN 241 00:11:47,462 --> 00:11:50,198 AND HAVE THEM PREPARE THE MENU 242 00:11:50,198 --> 00:11:52,500 AND THE ENTIRE MEAL ALONG WITH 243 00:11:52,500 --> 00:11:53,134 IT. 244 00:11:53,134 --> 00:11:55,537 BY WORKING TOGETHER AS FULL 245 00:11:55,537 --> 00:11:56,204 EQUAL PARTNERS YOU CAN MAKE 246 00:11:56,204 --> 00:11:58,273 TREMENDOUS ADVANCES. 247 00:11:58,273 --> 00:12:01,476 THE THIRD TAKE HOME MESSAGE IS 248 00:12:01,476 --> 00:12:02,744 WITH MODERN SCIENCE AND THE 249 00:12:02,744 --> 00:12:04,112 CHANGES THAT HAVE BEEN OCCURRING 250 00:12:04,112 --> 00:12:05,213 IN TECHNOLOGY WITH OUR 251 00:12:05,213 --> 00:12:06,615 UNDERSTANDING OF THE PAST FIVE 252 00:12:06,615 --> 00:12:10,452 OR 10 IS YEARS WE'RE ON THE CUSP 253 00:12:10,452 --> 00:12:13,688 OF A MAJOR REVOLUTION NOT ONLY 254 00:12:13,688 --> 00:12:15,056 UNDERSTANDING BASIC PHYSIOLOGY 255 00:12:15,056 --> 00:12:17,559 BUT UNDERSTANDING THERAPEUTICS 256 00:12:17,559 --> 00:12:18,927 FOR THE PATHOLOGIES. 257 00:12:18,927 --> 00:12:21,263 AND FROM THE WORK IN 258 00:12:21,263 --> 00:12:21,763 FIBROLAMELLAR WHICH IS 259 00:12:21,763 --> 00:12:26,501 RELATIVELY A RARE CANCER. 260 00:12:26,501 --> 00:12:28,737 IF YOU'RE NOT FAMILIAR IT'S 261 00:12:28,737 --> 00:12:32,474 FIRST DESCRIBED BACK IN THE LATE 262 00:12:32,474 --> 00:12:42,550 '50s ON THE RIGHT IS A 263 00:12:42,550 --> 00:12:47,589 HISTOPATHOLOGY AND SURROUNDED BY 264 00:12:47,589 --> 00:12:58,199 FIBROTIC BANDS, LAMELLAR AND 265 00:13:01,603 --> 00:13:03,138 THERE'S MISDIAGNOSIS. 266 00:13:03,138 --> 00:13:05,473 PEAK DETECTION IS 26 YEARS WITH 267 00:13:05,473 --> 00:13:08,677 MOST PATIENTS BETWEEN YEAR FIVE 268 00:13:08,677 --> 00:13:16,685 AND 40 YEARS OLD. 269 00:13:16,685 --> 00:13:20,055 IN THE U.S. IS 1 IN 5 MILLION 270 00:13:20,055 --> 00:13:22,157 BUT IT'S BEEN MISSED AND UNDER 271 00:13:22,157 --> 00:13:22,624 DIAGNOSED. 272 00:13:22,624 --> 00:13:25,694 IT PRESENTS AS PRIMELY LIVER 273 00:13:25,694 --> 00:13:27,429 TUMOR AS A SINGLE MASS. 274 00:13:27,429 --> 00:13:30,265 THERE'S NO UNDERLYING DISEASE. 275 00:13:30,265 --> 00:13:32,600 FEW SYMPTOMS NOT ASSOCIATED WITH 276 00:13:32,600 --> 00:13:33,568 OTHER RISK FACTORS. 277 00:13:33,568 --> 00:13:37,939 IT'S CODIFIED AS A SUB VARIANT 278 00:13:37,939 --> 00:13:40,442 OF A CARCINOMA. 279 00:13:40,442 --> 00:13:42,377 AS A RESULT MOST PATIENTS ARE 280 00:13:42,377 --> 00:13:45,547 STILL TREATED AS A THEY ARE HAVE 281 00:13:45,547 --> 00:13:47,282 AHEMATO CARCINOMA. 282 00:13:47,282 --> 00:13:50,919 THERE'S NO SYSTEMIC CHEMO OR 283 00:13:50,919 --> 00:13:51,986 THERAPIES AND THE CURRENT 284 00:13:51,986 --> 00:13:52,554 MANAGEMENT IS RESECTION. 285 00:13:52,554 --> 00:13:54,422 WHEN WE STARTED WORKING ON THIS 286 00:13:54,422 --> 00:13:57,292 A DECADE AGO IT WAS NOT OWN AS 287 00:13:57,292 --> 00:13:59,327 ONE DISEASE OR MA MANY DISEASES 288 00:13:59,327 --> 00:14:03,031 WITH A COMMON HISTOPATHOLOGY. 289 00:14:03,031 --> 00:14:11,039 IS IT GENETICALLY INHERITED OR 290 00:14:11,039 --> 00:14:12,240 SOMATICALLY ACQUIRED. 291 00:14:12,240 --> 00:14:15,577 AND APRIL 8, 2008, MY DAUGHTER 292 00:14:15,577 --> 00:14:19,047 IS 12 AT THE TIME WAS DIAGNOSED 293 00:14:19,047 --> 00:14:21,549 WITH FIBROLAMELLAR CARCINOMA. 294 00:14:21,549 --> 00:14:24,719 AT THE TIME IF YOU LOOKED AT THE 295 00:14:24,719 --> 00:14:29,557 CURVE FOR SURVIVAL SHE HAD ZERO 296 00:14:29,557 --> 00:14:31,993 PERCENT SURVIVAL AT FIVE YEARS. 297 00:14:31,993 --> 00:14:36,231 I SHOULD TO STUDY SINGLE EVENTS, 298 00:14:36,231 --> 00:14:39,768 SINGLE VESICLES FUSING. 299 00:14:39,768 --> 00:14:41,002 I SAID WHY TO THE TAKE ONE 300 00:14:41,002 --> 00:14:43,838 SINGLE CANCER AND STUDY THAT IN 301 00:14:43,838 --> 00:14:47,108 DETAIL INSTEAD OF JOIN ALL 302 00:14:47,108 --> 00:14:53,548 HEEMENT -- HEPATOCARCINOMAS 303 00:14:53,548 --> 00:14:55,350 TOGETHER AND SEE WHAT WE CAN 304 00:14:55,350 --> 00:14:55,550 LEARN. 305 00:14:55,550 --> 00:14:57,218 BUT THERE'S PROBLEMS WITH 306 00:14:57,218 --> 00:14:59,154 STUDYING A RARE DISEASE. 307 00:14:59,154 --> 00:15:00,054 THERE'S A LACK OF INFORMATION 308 00:15:00,054 --> 00:15:01,556 AND LACK OF TOOLS. 309 00:15:01,556 --> 00:15:03,992 THERE'S TOO FEW SAMPLES IF IT'S 310 00:15:03,992 --> 00:15:06,327 VERY RARE AND TOO LITTLE 311 00:15:06,327 --> 00:15:06,561 FUNDING. 312 00:15:06,561 --> 00:15:07,662 MY EARLY GRANT SPACE CAME BACK 313 00:15:07,662 --> 00:15:10,365 WITH A REVIEW OF THIS IS 314 00:15:10,365 --> 00:15:13,668 WONDERFUL SCIENCE BUT TOO RARE 315 00:15:13,668 --> 00:15:21,309 TO BE SIGNIFICANT. 316 00:15:21,309 --> 00:15:24,379 SO WHY STUDY IT? 317 00:15:24,379 --> 00:15:28,483 YOU HEARD IT WAS PRECISELY 318 00:15:28,483 --> 00:15:31,319 DEFINED TO LEARNING THINGS VERY 319 00:15:31,319 --> 00:15:32,987 QUICKLY AND YOU CAN MAKE RAPID 320 00:15:32,987 --> 00:15:33,555 PROGRESS. 321 00:15:33,555 --> 00:15:36,825 FOR EXAMPLE, FROM STUDYING OTHER 322 00:15:36,825 --> 00:15:38,560 RARE DISEASES LIKE GLIAL 323 00:15:38,560 --> 00:15:41,062 BLASTOMA WE LEARNED ABOUT 324 00:15:41,062 --> 00:15:42,630 HYDROGENASES IN CANCER AND WE 325 00:15:42,630 --> 00:15:44,299 LEARNED ABOUT THE TUMOR 326 00:15:44,299 --> 00:15:44,999 SUPPRESSERS. 327 00:15:44,999 --> 00:15:46,701 SO OUR APPROACH WAS TO PART 328 00:15:46,701 --> 00:15:48,436 ANYONE WITH PATIENTS THROUGH 329 00:15:48,436 --> 00:15:49,838 SOCIAL MEDIA. 330 00:15:49,838 --> 00:15:53,374 FIRST STEP WAS MY DAUGHTER MADE 331 00:15:53,374 --> 00:15:55,176 A VIDEO ON YOUTUBE WITH ANOTHER 332 00:15:55,176 --> 00:15:55,443 PATIENT. 333 00:15:55,443 --> 00:16:01,549 >> WHEN I WAS 12 I WAS DIAGNOSED 334 00:16:01,549 --> 00:16:05,153 WITH FIBROLA MELLER. 335 00:16:05,153 --> 00:16:07,655 PEOPLE ARE WORKING ON IT AND 336 00:16:07,655 --> 00:16:08,823 PEOPLE ARE TRYING TO FIND A CURE 337 00:16:08,823 --> 00:16:11,292 AND TRYING TO HELP UNDERSTAND 338 00:16:11,292 --> 00:16:13,061 WHAT THE CANCER IS. 339 00:16:13,061 --> 00:16:14,963 AND WE NEED TISSUE SAMPLES. 340 00:16:14,963 --> 00:16:17,799 SO YOU DO HAVE THE RIGHT TO TAKE 341 00:16:17,799 --> 00:16:19,167 YOUR OWN TISSUE. 342 00:16:19,167 --> 00:16:21,236 YOU CAN ASK A DOCTOR TO SEND IT 343 00:16:21,236 --> 00:16:22,871 TO RESEARCHERS SO PEOPLE CAN TRY 344 00:16:22,871 --> 00:16:23,438 TO DEVELOP A CURE FOR THIS 345 00:16:23,438 --> 00:16:28,209 CANCER. 346 00:16:28,209 --> 00:16:29,811 SO FROM REACHING OUT THROUGH 347 00:16:29,811 --> 00:16:33,014 SOCIAL MEDIA WE GOT INFORMATION 348 00:16:33,014 --> 00:16:35,683 FROM MANY PATIENTS. 349 00:16:35,683 --> 00:16:37,652 AND WE NOW HAVE DATA FROM 350 00:16:37,652 --> 00:16:38,920 HUNDREDS OF PATIENTS OVER 20 351 00:16:38,920 --> 00:16:40,054 COUNTRIES. 352 00:16:40,054 --> 00:16:43,925 THIS IS A REGISTRY PAGE WE SET 353 00:16:43,925 --> 00:16:44,559 UP. 354 00:16:44,559 --> 00:16:51,699 IT'S A NON-PROFIT 5013C RAN BY 355 00:16:51,699 --> 00:16:52,800 PATIENTS AND FAMILIES AND 356 00:16:52,800 --> 00:16:56,070 THERE'S A LIMITED NUMBER IN ANY 357 00:16:56,070 --> 00:16:56,971 ONE COUNTRY. 358 00:16:56,971 --> 00:16:59,140 BY HAVING THE PATIENTS AND 359 00:16:59,140 --> 00:17:00,775 FAMILY MEMBERS RUNNING THIS 360 00:17:00,775 --> 00:17:02,510 MEANS WE CAN FOLLOW PATIENTS 361 00:17:02,510 --> 00:17:04,178 BETWEEN INSTITUTIONS EVEN FROM 362 00:17:04,178 --> 00:17:05,413 COUNTRY TO COUNTRY WHICH ALLOWS 363 00:17:05,413 --> 00:17:09,150 FOR LONGER OUTCOMES AND MORE 364 00:17:09,150 --> 00:17:11,819 NUMBERS BEING INVOLVED. 365 00:17:11,819 --> 00:17:13,922 UNLIKE MOST DATABASES SINCE IT'S 366 00:17:13,922 --> 00:17:14,856 PATIENTS FOLLOWING PATIENTS WE 367 00:17:14,856 --> 00:17:17,058 CAN FOLLOW-UP AND AVOID 368 00:17:17,058 --> 00:17:17,358 DUPLICATION. 369 00:17:17,358 --> 00:17:19,294 IT ALSO MEANS OVER TIME THE 370 00:17:19,294 --> 00:17:20,929 MOLECULAR CHARACTERIZATION OF 371 00:17:20,929 --> 00:17:22,931 CHANGES YOU CAN EDIT THE DATA. 372 00:17:22,931 --> 00:17:26,801 IT'S RUN BY THE PATIENT FAMILY 373 00:17:26,801 --> 00:17:27,569 COMMUNITY WITH THE PROMISE 374 00:17:27,569 --> 00:17:29,571 PATIENT DATA WON'T BE SOLD AND 375 00:17:29,571 --> 00:17:32,807 WE GET HIGH BUY IN FROM 376 00:17:32,807 --> 00:17:33,074 PATIENTS. 377 00:17:33,074 --> 00:17:35,977 WE GOT TOGETHER WITH PATIENTS, 378 00:17:35,977 --> 00:17:38,546 ONCOLOGISTS AND PATHOLOGISTS AND 379 00:17:38,546 --> 00:17:40,715 RADIOLOGISTS AND CAME UP WITH 380 00:17:40,715 --> 00:17:42,383 QUESTIONS OF CONCERN TO OUR 381 00:17:42,383 --> 00:17:45,186 MEMBERS IN THE REGISTRY NOW PART 382 00:17:45,186 --> 00:17:46,387 OF THE MEDICAL RECORD. 383 00:17:46,387 --> 00:17:48,189 NOW, IN ADDITION TO THEM GIVING 384 00:17:48,189 --> 00:17:49,390 THEIR OWN INFORMATION IN 385 00:17:49,390 --> 00:17:51,359 RESPONSE TO QUESTIONS, WE'RE 386 00:17:51,359 --> 00:17:54,462 LINKED BETWEEN THEM AND RESEARCH 387 00:17:54,462 --> 00:17:55,496 CLINICAL COMMUNITY. 388 00:17:55,496 --> 00:17:59,667 FOR EXAMPLE, WE HAVE FREQUENTLY 389 00:17:59,667 --> 00:18:03,037 ASKED QUESTIONS ABOUT 390 00:18:03,037 --> 00:18:06,908 FIBROLAMELLAR CARCINOMA, 391 00:18:06,908 --> 00:18:08,076 DICTIONARIES OF KEY TERMS AND 392 00:18:08,076 --> 00:18:09,477 INFORMATION ON THE SCIENCE AND 393 00:18:09,477 --> 00:18:11,446 VIDEOS HOW IT OCCURS. 394 00:18:11,446 --> 00:18:13,381 WE HAVE AN INTRODUCTION TO THE 395 00:18:13,381 --> 00:18:13,681 LITERATURE. 396 00:18:13,681 --> 00:18:17,218 IF YOU CLICK YOU CAN DOWNLOAD A 397 00:18:17,218 --> 00:18:18,786 VIDEO HOW TO GET INTO PUB MED. 398 00:18:18,786 --> 00:18:19,921 WHAT IS PUB MED? 399 00:18:19,921 --> 00:18:21,556 HOW TO FIND ARTICLES. 400 00:18:21,556 --> 00:18:22,924 WHAT IS A PDF? 401 00:18:22,924 --> 00:18:25,927 HOW DO YOU GET A PDF READER? 402 00:18:25,927 --> 00:18:32,667 HOW DO YOU CONTACT AUTHORS TO 403 00:18:32,667 --> 00:18:34,002 GET COPIES. 404 00:18:34,002 --> 00:18:36,638 WE HAVE VIDEOS OF THE ARTICLES 405 00:18:36,638 --> 00:18:40,074 SUMMARIZING THE RESULTS AND THIS 406 00:18:40,074 --> 00:18:44,012 IS MADE BY MY LAB. 407 00:18:44,012 --> 00:18:47,515 >> IN ORDER TO CONFIRM THE 408 00:18:47,515 --> 00:18:49,951 CHIMERA THEY EDIT THE GENES OF 409 00:18:49,951 --> 00:18:53,121 ADULT MICE USING A NEW CRISPR 410 00:18:53,121 --> 00:18:54,622 TECHNOLOGY AND TOOK THE DNA OF A 411 00:18:54,622 --> 00:18:57,825 MICE AND CREATED THE SAME 412 00:18:57,825 --> 00:19:01,963 DELETION FOUND IN FIBROLAMELLAR 413 00:19:01,963 --> 00:19:02,997 PATIENTS AND WITHIN MONTHS THE 414 00:19:02,997 --> 00:19:05,099 CANCER WITH THE DELETION HAVE 415 00:19:05,099 --> 00:19:06,668 THE CANCER. 416 00:19:06,668 --> 00:19:09,070 THIS EXPERIMENT ONLY TELLS YOU 417 00:19:09,070 --> 00:19:11,572 THE DNA DELETION IS IMPORTANT. 418 00:19:11,572 --> 00:19:14,342 IT DOESN'T TELL YOU WHETHER THE 419 00:19:14,342 --> 00:19:19,947 CHIMERA OR GENES ARE THE CAUSE 420 00:19:19,947 --> 00:19:25,920 AND THEY ADDED EXTRA DNA WITH 421 00:19:25,920 --> 00:19:28,990 CHIMERA AND THE MICE GOT 422 00:19:28,990 --> 00:19:29,457 FIBROLAMELLAR TOO. 423 00:19:29,457 --> 00:19:32,293 >> THE IDEA IS TO MAKE THIS 424 00:19:32,293 --> 00:19:34,362 SCIENCE ACCESSIBLE TO THE 425 00:19:34,362 --> 00:19:35,697 PATIENTS. 426 00:19:35,697 --> 00:19:37,565 ONE OF OUR STRONG BELIEFS IS IN 427 00:19:37,565 --> 00:19:39,634 THE LAB IS WE MAKE STRONG 428 00:19:39,634 --> 00:19:39,934 SACRIFICES. 429 00:19:39,934 --> 00:19:42,370 THE BIGGEST ARE MADE BY THE 430 00:19:42,370 --> 00:19:42,637 PATIENTS. 431 00:19:42,637 --> 00:19:46,808 IT'S THE PATIENTS GIVING THEIR 432 00:19:46,808 --> 00:19:50,278 TISSUE, THEIR BLOOD, SHARING 433 00:19:50,278 --> 00:19:51,879 RECORDS AND IN MANY CASES THEY 434 00:19:51,879 --> 00:19:54,215 WORK AT THE BENCH DOING THE 435 00:19:54,215 --> 00:19:54,482 RESEARCH. 436 00:19:54,482 --> 00:19:56,017 WE HAVE AN OBLIGATION TO MAKE 437 00:19:56,017 --> 00:19:58,619 THIS SCIENCE AS ACCESSIBLE AS 438 00:19:58,619 --> 00:19:58,886 POSSIBLE. 439 00:19:58,886 --> 00:20:01,422 OUR REGISTRY IS IRB APPROVED AT 440 00:20:01,422 --> 00:20:03,291 THE OF THE OF A VARIETY OF 441 00:20:03,291 --> 00:20:05,560 CLINICIANS WE MOVED THE ENTIRE 442 00:20:05,560 --> 00:20:08,830 PLATFORM TO RED CAP AND HAVE 443 00:20:08,830 --> 00:20:10,598 EPIDEMIOLOGISTS AND 444 00:20:10,598 --> 00:20:12,533 STATISTICIANS REVIEWING THE 445 00:20:12,533 --> 00:20:13,101 DATA. 446 00:20:13,101 --> 00:20:14,235 WE FOUND CLUSTERS OF PATIENTS 447 00:20:14,235 --> 00:20:16,370 NEAR EACH OTHER AND THE 448 00:20:16,370 --> 00:20:17,572 CLUSTERING DOES NOT FOLLOW 449 00:20:17,572 --> 00:20:18,973 POPULATION DENSITY AND LEADING 450 00:20:18,973 --> 00:20:20,308 TO ALL SORTS OF STUDIES. 451 00:20:20,308 --> 00:20:23,277 WHAT'S IN COMMON TO THE PATIENTS 452 00:20:23,277 --> 00:20:25,413 THAT LIVE NEAR EACH OTHER AND 453 00:20:25,413 --> 00:20:28,416 MUTATIONAL SIGNATURES IN THE 454 00:20:28,416 --> 00:20:29,283 DNA. 455 00:20:29,283 --> 00:20:30,952 AS THE EXTENSIVE INFORMATION OF 456 00:20:30,952 --> 00:20:32,487 PATIENT SURVIVAL. 457 00:20:32,487 --> 00:20:34,789 WE FOUND SURVIVAL DOESN'T 458 00:20:34,789 --> 00:20:39,460 CORRELATE WITH AGE OF DIAGNOSIS. 459 00:20:39,460 --> 00:20:42,497 WOMEN ARE MORE LIKELY TO GET IT 460 00:20:42,497 --> 00:20:44,532 MORE THAN MEN, ROUGHLY 60% AND 461 00:20:44,532 --> 00:20:46,000 WOMEN HAVE A BETTER SURVIVAL 462 00:20:46,000 --> 00:20:46,968 THAN MEN. 463 00:20:46,968 --> 00:20:49,871 THESE ARE THE OUTCOMES. 464 00:20:49,871 --> 00:20:51,773 WOMEN ARE MORE AWARE OF THEIR 465 00:20:51,773 --> 00:20:54,442 BODIES AND DIAGNOSED EARLIER AND 466 00:20:54,442 --> 00:20:55,643 DIAGNOSED AT THE SAME AGE LED TO 467 00:20:55,643 --> 00:21:01,549 STUDIES LOOKING AT THE ROLE OF 468 00:21:01,549 --> 00:21:04,719 HORMONES AND INACTIVATION OF 469 00:21:04,719 --> 00:21:07,922 GENES ON THE X CHROMOSOME. 470 00:21:07,922 --> 00:21:09,557 AND I WOULD HAVE THOUGHT THE 471 00:21:09,557 --> 00:21:11,225 BIGGER THE TUMOR THE WORSE 472 00:21:11,225 --> 00:21:15,029 CHANCE OF SURVIVAL BUT AT THE 473 00:21:15,029 --> 00:21:18,633 DON'T CORRELATE AND METASTASIS 474 00:21:18,633 --> 00:21:20,935 DON'T CORRELATE TO TUMOR SIZE. 475 00:21:20,935 --> 00:21:22,703 WHAT CORRELATED THOUGH IS THE 476 00:21:22,703 --> 00:21:24,138 EXTENT OF SPREAD OF DISEASE. 477 00:21:24,138 --> 00:21:25,840 WAS THERE INVOLVEMENT OUTSIDE 478 00:21:25,840 --> 00:21:26,507 THE LIVER? 479 00:21:26,507 --> 00:21:29,577 AND THE TUMORS ARE OFTEN IN THE 480 00:21:29,577 --> 00:21:33,548 LIVER AT THE TIME. 481 00:21:33,548 --> 00:21:35,850 PATIENTS WHO GOT SURGERY WHO GOT 482 00:21:35,850 --> 00:21:40,721 THE BEST AND THOSE WHO JUST HAD 483 00:21:40,721 --> 00:21:42,089 SYSTEMIC SURGERIES DID BETTER 484 00:21:42,089 --> 00:21:44,592 THAN THOSE WHO DIDN'T AT ALL AND 485 00:21:44,592 --> 00:21:46,494 MOST THE PATIENTS WITH TUMORS 486 00:21:46,494 --> 00:21:48,229 OUTSIDE THE LIVER HAVE BEEN TOLD 487 00:21:48,229 --> 00:21:53,201 THE TUMOR IS NOT OPERABLE. 488 00:21:53,201 --> 00:21:54,368 CANNOT BE REMOVED AND WE 489 00:21:54,368 --> 00:21:56,003 ENCOURAGED THEM TO GET A SECOND 490 00:21:56,003 --> 00:21:57,538 OPINION AND THEN THEIR SURVIVAL 491 00:21:57,538 --> 00:22:00,942 IS MUCH BETTER THAN OTHERS. 492 00:22:00,942 --> 00:22:02,877 IT'S A STRONG ARGUMENT FOR GOING 493 00:22:02,877 --> 00:22:05,546 OUT FOR SECOND OPINION AT ALL 494 00:22:05,546 --> 00:22:06,080 TIMES. 495 00:22:06,080 --> 00:22:09,350 WE PULLED OUT A FEW DOZEN 496 00:22:09,350 --> 00:22:12,653 PATIENTS WHO RECEIVED CHECKPOINT 497 00:22:12,653 --> 00:22:15,089 INHIBITERS AND THE MEMBERS 498 00:22:15,089 --> 00:22:16,657 RUNNING THE REGISTRY AT JOHNS 499 00:22:16,657 --> 00:22:17,558 HOPKINS TOOK ALL THE SCANS OF 500 00:22:17,558 --> 00:22:20,895 THE MEDICAL RECORDS AND ONE TEAM 501 00:22:20,895 --> 00:22:21,529 READING AND EVALUATING THE 502 00:22:21,529 --> 00:22:25,700 OUTCOMES. 503 00:22:25,700 --> 00:22:27,835 WHAT KIND OF ANALYSIS HAVE WE 504 00:22:27,835 --> 00:22:29,337 GOTTEN IN WHOLE GENOME ANALYSIS 505 00:22:29,337 --> 00:22:31,973 AND ANALYZED THE GENE EXPRESSION 506 00:22:31,973 --> 00:22:35,776 AND TRANSCRIPTOME AND PROTEOMICS 507 00:22:35,776 --> 00:22:38,279 AND FOR BACKGROUND FOR THOSE NOT 508 00:22:38,279 --> 00:22:39,914 FAMILIAR AGAIN ALL THE GENETIC 509 00:22:39,914 --> 00:22:41,883 MATERIAL IS STORED IN TWO VERY 510 00:22:41,883 --> 00:22:43,818 LONG STRANDS OF DNA AND THINGS 511 00:22:43,818 --> 00:22:45,353 WE CALL THE CHROMOSOMES. 512 00:22:45,353 --> 00:22:48,155 IT'S ON EACH CHROME IT WILL 513 00:22:48,155 --> 00:22:49,290 YOU'LL HAVE FOR EXAMPLE A GREEN 514 00:22:49,290 --> 00:22:53,394 GENE AND HERE IS AN ORANGE GREEN 515 00:22:53,394 --> 00:22:55,930 AND INCLUDED IN SHORT SNIPPETS 516 00:22:55,930 --> 00:22:59,100 AND WHAT IS COLORED IS THE 517 00:22:59,100 --> 00:23:01,202 REASON FOR THE GENE. 518 00:23:01,202 --> 00:23:02,536 ARE YOU STILL HEARING ME? 519 00:23:02,536 --> 00:23:05,840 I HEARD BACKGROUND NOISE. 520 00:23:05,840 --> 00:23:09,477 AND IN BETWEEN THERE'S REGIONS 521 00:23:09,477 --> 00:23:10,678 LINKING THEM TOGETHER NOT 522 00:23:10,678 --> 00:23:11,045 CODING. 523 00:23:11,045 --> 00:23:16,183 YOU MAKE A COPY OF THE DNA AND 524 00:23:16,183 --> 00:23:17,852 YOU GO THROUGH COPYING IT AND 525 00:23:17,852 --> 00:23:23,257 MAKE WHAT'S CALLED A MESSENGER 526 00:23:23,257 --> 00:23:27,061 DNA AND THEN THE CELL SPLICES 527 00:23:27,061 --> 00:23:29,530 ALL THE PIECES IN BETWEEN TO GET 528 00:23:29,530 --> 00:23:38,005 THE MESSENGER RNA TO GO IN THE 529 00:23:38,005 --> 00:23:39,907 PROTEINS AND THERE'S A DELETION 530 00:23:39,907 --> 00:23:41,509 THAT FUSES THEM TOGETHER. 531 00:23:41,509 --> 00:23:43,277 YOU HAVE THE START OF THE GREEN 532 00:23:43,277 --> 00:23:46,614 GENE FUSED WITH THE BODY OF THIS 533 00:23:46,614 --> 00:23:47,515 ORANGE GENE. 534 00:23:47,515 --> 00:23:57,558 WE CALL THIS CHIMERIC FROM 535 00:23:57,558 --> 00:24:01,562 MYTHOLOGY AND IT SPLICES OUT IN 536 00:24:01,562 --> 00:24:04,598 BETWEEN AND THE MESSENGER RNA 537 00:24:04,598 --> 00:24:06,067 LEAVES THE NUCLEUS AND GOES OUT 538 00:24:06,067 --> 00:24:07,702 TO THE PERIPHERY WITH THE 539 00:24:07,702 --> 00:24:11,238 MACHINE IN RED CALLED THE 540 00:24:11,238 --> 00:24:11,505 RIBOSOMES. 541 00:24:11,505 --> 00:24:14,041 THEY MAKE THEM INTO PROTEINS. 542 00:24:14,041 --> 00:24:17,278 WHEN THE CHIMERIC AND FUSION 543 00:24:17,278 --> 00:24:19,847 RIBOSOMES COME OUT THEY MAKE A 544 00:24:19,847 --> 00:24:22,016 FUSION PROTEIN SO IT'S A 545 00:24:22,016 --> 00:24:22,249 CHIMERA. 546 00:24:22,249 --> 00:24:29,256 A MIX OF TWO PROTEINS TOGETHER. 547 00:24:29,256 --> 00:24:32,059 WE JUST NEED TO EXPRESS THE 548 00:24:32,059 --> 00:24:34,695 FUSION PROTEIN TO GET THE 549 00:24:34,695 --> 00:24:36,797 COMPLETE PHENOTYPE OF 550 00:24:36,797 --> 00:24:37,131 FIBROLAMELLAR. 551 00:24:37,131 --> 00:24:40,267 WE FOUND THIS IN EVERY PATIENT. 552 00:24:40,267 --> 00:24:41,635 IF WE RECREATE THE SAME DELETION 553 00:24:41,635 --> 00:24:45,573 IN THE LIVERS OF MICE WE GET 554 00:24:45,573 --> 00:24:49,443 TUMORS THAT LOOK LIKE 555 00:24:49,443 --> 00:24:50,945 FIBROLAMELLAR CARCINOMA AND ALL 556 00:24:50,945 --> 00:24:51,912 THE GENE EXPRESSION AND NICE DIE 557 00:24:51,912 --> 00:24:54,615 OF THE TUMORS. 558 00:24:54,615 --> 00:24:57,551 IF WE RECREATE THE SAME DELETION 559 00:24:57,551 --> 00:25:05,559 IN PRIMARY HEPATOCYTES THEY HAVE 560 00:25:05,559 --> 00:25:11,032 THE CHANGES AND GENE EXPRESSION. 561 00:25:11,032 --> 00:25:14,335 SO WHAT ELSE DID WE LEARN? 562 00:25:14,335 --> 00:25:18,606 WE COMPARED IT TO THE TISSUE AND 563 00:25:18,606 --> 00:25:24,078 HAVE LOW LEVEL OF SINGLE NU 564 00:25:24,078 --> 00:25:26,213 NUCLEOTIDE MUTATIONS. 565 00:25:26,213 --> 00:25:28,682 THERE'S LOW LEVELS OF WHAT ARE 566 00:25:28,682 --> 00:25:30,918 CALLED STRUCTURE VARIANTS AND 567 00:25:30,918 --> 00:25:32,420 AMPLIFICATIONS OR GENES BEING 568 00:25:32,420 --> 00:25:32,953 INVERTED. 569 00:25:32,953 --> 00:25:34,755 WE LOOK TO THE TRANSCRIPTOME AND 570 00:25:34,755 --> 00:25:37,191 ANALYSIS AND ALL THE GENES BEING 571 00:25:37,191 --> 00:25:38,659 EXPRESSED AND WE HAD THOUSANDS 572 00:25:38,659 --> 00:25:40,694 OF TRANSCRIPTS THAT CHANGED 573 00:25:40,694 --> 00:25:41,796 SIGNIFICANTLY AND THE CHANGES 574 00:25:41,796 --> 00:25:45,299 WERE SIMILAR FROM PATIENT TO. 575 00:25:45,299 --> 00:25:45,566 PATIENT. 576 00:25:45,566 --> 00:25:48,903 HERE A SUMMARY OF DATA FROM 577 00:25:48,903 --> 00:25:50,037 PATIENTS FROM SEVEN LABS. 578 00:25:50,037 --> 00:25:50,838 MOSTLY OUR LAB. 579 00:25:50,838 --> 00:25:57,311 IT'S A CLUSTERING OF ALL THE 580 00:25:57,311 --> 00:25:58,412 TRANSCRIPTS COMPARED TO THE 581 00:25:58,412 --> 00:25:59,780 NORMAL ADJACENT TUMOR. 582 00:25:59,780 --> 00:26:02,783 ALL THE TUMORS HAVE ALL THE SAME 583 00:26:02,783 --> 00:26:05,052 CHANGES IN THE TRANSCRIPTOME 584 00:26:05,052 --> 00:26:06,487 COMPARED TO THE NORMAL. 585 00:26:06,487 --> 00:26:09,557 THERE'S ALMOST NO DIFFERENCE. 586 00:26:09,557 --> 00:26:14,228 IT'S A VERY HOMOGENEOUS DISEASE 587 00:26:14,228 --> 00:26:24,238 AND HERE'S WHERE ALL THE HEP 588 00:26:24,238 --> 00:26:32,113 HEPATOSILLIC TUMOR AND IT'S V 589 00:26:32,113 --> 00:26:42,556 VERY -- HEEL HEME GENEOUS 590 00:26:50,231 --> 00:26:51,432 PATIENTS. 591 00:26:51,432 --> 00:26:56,170 BECAUSE OF THE HOMOGENEITY AND 592 00:26:56,170 --> 00:26:59,507 IF IT CAN WORK IN ONE PATIENT IT 593 00:26:59,507 --> 00:27:02,343 HAS POTENTIAL TO WORK ON ALL 594 00:27:02,343 --> 00:27:03,511 PATIENTS. 595 00:27:03,511 --> 00:27:07,114 WE GOT WE HAVE TO SHARE WITH THE 596 00:27:07,114 --> 00:27:08,048 PATIENT COMMUNITY. 597 00:27:08,048 --> 00:27:10,251 WE CREATED AN APP PATIENTS CAN 598 00:27:10,251 --> 00:27:12,786 GO INTO AND WE DESCRIBE TO THEM 599 00:27:12,786 --> 00:27:17,358 WHAT ARE THE CHANGES IN THE 600 00:27:17,358 --> 00:27:18,025 TRANSCRIPTOME. 601 00:27:18,025 --> 00:27:19,760 WHY SHOULD THAT BE OF CHANGES 602 00:27:19,760 --> 00:27:22,530 AND WE HAVE A FIBROLAMELLAR 603 00:27:22,530 --> 00:27:23,898 CHANGES AND THE CLASSIC CHANGES 604 00:27:23,898 --> 00:27:25,766 AND THE TUTORIAL HOW TO GO 605 00:27:25,766 --> 00:27:29,537 THROUGH AND EXPLORE THE CHANGES 606 00:27:29,537 --> 00:27:34,975 IN THE TRANSCRIPTOMES. 607 00:27:34,975 --> 00:27:37,144 THIS IS NOW SHOWING THE RESULTS 608 00:27:37,144 --> 00:27:40,414 FROM SEVEN DIFFERENT LABS. 609 00:27:40,414 --> 00:27:42,616 AGAIN, VERY CONSISTENT RESULTS 610 00:27:42,616 --> 00:27:45,753 ACROSS ALL THE LABORATORIES OR 611 00:27:45,753 --> 00:27:50,724 THE CHANGES BETWEEN THE PRIMARY 612 00:27:50,724 --> 00:27:59,300 AND METASTASIS FOR THE TUMORS 613 00:27:59,300 --> 00:28:00,301 AND YOU CAN PROBE THIS WITH ANY 614 00:28:00,301 --> 00:28:01,569 ONE OF THE TRANSCRIPTS. 615 00:28:01,569 --> 00:28:05,539 ONE OF THE DIFFERENCES IN 616 00:28:05,539 --> 00:28:09,677 FIBROLAMELLAR YOU SEE HOW IT 617 00:28:09,677 --> 00:28:14,148 INCREASES COMPARED TO HEP 618 00:28:14,148 --> 00:28:16,317 HEPATOBLASTOMA AND WE'RE TRYING 619 00:28:16,317 --> 00:28:20,955 TO MAKE THIS ACCESSIBLE TO THE 620 00:28:20,955 --> 00:28:22,156 COMMUNITY AND WHAT WE'RE DOING 621 00:28:22,156 --> 00:28:23,090 AND WHY IT'S IMPORTANT AND TO 622 00:28:23,090 --> 00:28:27,228 GET THEIR INPUT. 623 00:28:27,228 --> 00:28:29,263 I WANT TO FOCUS ON THERAPEUTICS 624 00:28:29,263 --> 00:28:31,365 AND THE DEVELOP THERAPEUTICS. 625 00:28:31,365 --> 00:28:32,967 YOU NEED GOOD MODEL SYSTEMS FOR 626 00:28:32,967 --> 00:28:33,901 TESTING THEM. 627 00:28:33,901 --> 00:28:36,170 WE'VE BEEN USING THREE KEY 628 00:28:36,170 --> 00:28:37,504 SYSTEMS IN OUR LAB. 629 00:28:37,504 --> 00:28:39,740 ONE ARE ORGANOIDS. 630 00:28:39,740 --> 00:28:41,141 SMALL MINI LIVERS, IF YOU WISH 631 00:28:41,141 --> 00:28:43,444 GO IN A DISH. 632 00:28:43,444 --> 00:28:44,945 I WON'T GO INTO DETAIL IN THAT 633 00:28:44,945 --> 00:28:47,147 TODAY BECAUSE I WON'T USE THIS 634 00:28:47,147 --> 00:28:48,449 IN THE PRESENTATION, THEY'RE 635 00:28:48,449 --> 00:28:51,719 TESTING CELLS DIRECTLY FROM 636 00:28:51,719 --> 00:28:53,887 PATIENTS. 637 00:28:53,887 --> 00:28:57,258 WE HAVE A LAB AND WE'RE 638 00:28:57,258 --> 00:29:00,261 SCREENING THEM AGAINST VARIOUS 639 00:29:00,261 --> 00:29:03,831 AGENTS OR PLANT TUMORS IN MICE. 640 00:29:03,831 --> 00:29:06,033 THEY'RE CALLED PATIENT DERIVED 641 00:29:06,033 --> 00:29:08,035 XENO GRAPHS. 642 00:29:08,035 --> 00:29:10,371 YOU WANT TO KNOW HOW FAITHFUL IS 643 00:29:10,371 --> 00:29:11,839 REPORTING THE BEHAVIOR OF THE 644 00:29:11,839 --> 00:29:14,642 TUMORS IN THE PATIENTS. 645 00:29:14,642 --> 00:29:18,279 SO THERE'S A SERIOUS CRITERIA WE 646 00:29:18,279 --> 00:29:18,712 USE. 647 00:29:18,712 --> 00:29:22,650 IF YOU LOOK AT THE HISTOLOGY TO 648 00:29:22,650 --> 00:29:23,651 ABOUT WHAT EXTEND ARE THE SAME 649 00:29:23,651 --> 00:29:27,554 FROM THE ORIGINAL TUMORS IN THE 650 00:29:27,554 --> 00:29:27,921 PATIENTS? 651 00:29:27,921 --> 00:29:30,591 WE ONLY USE ONES WHICH CLOSELY 652 00:29:30,591 --> 00:29:32,159 RECAPITULATE WHAT YOU SEE IN THE 653 00:29:32,159 --> 00:29:33,227 PATIENTS. 654 00:29:33,227 --> 00:29:35,029 IF YOU LOOK FOR THE CHIMERIC 655 00:29:35,029 --> 00:29:38,565 FUSION TRANSCRIPT, IS IT THERE? 656 00:29:38,565 --> 00:29:39,533 IT'S ALWAYS THERE IN THE MICE 657 00:29:39,533 --> 00:29:41,535 AND PASSAGES OF THE TUMORS IN 658 00:29:41,535 --> 00:29:41,769 MICE. 659 00:29:41,769 --> 00:29:44,171 DO WE SEE THE FUSION PROTEINS? 660 00:29:44,171 --> 00:29:49,610 HERE'S THE NATIVE PROTEIN. 661 00:29:49,610 --> 00:29:50,811 TWO GENES ARE FUSED TOGETHER AND 662 00:29:50,811 --> 00:29:52,446 THE FRONT END IS FROM A HEAT 663 00:29:52,446 --> 00:29:55,316 SHOCK PROTEIN AND THE BULK IS 664 00:29:55,316 --> 00:29:59,420 CALLED THE CATALYTIC SUBUNIT OF 665 00:29:59,420 --> 00:30:01,322 A PROTEIN KINASE A. 666 00:30:01,322 --> 00:30:04,391 IT'S AN ENZYME A MACHINE THAT 667 00:30:04,391 --> 00:30:05,359 WORKS IN THE CELL BY MODIFYING 668 00:30:05,359 --> 00:30:07,494 OTHER MOLECULES AROUND IT. 669 00:30:07,494 --> 00:30:11,865 YOU CAN MODIFY SUGARS, PROTEINS, 670 00:30:11,865 --> 00:30:13,133 LIPIDS, BY PUTTING A PHOSPHATE 671 00:30:13,133 --> 00:30:14,735 ON THEM BY ACTIVATE OR 672 00:30:14,735 --> 00:30:15,869 INACTIVATE THEM. 673 00:30:15,869 --> 00:30:19,606 THE BULK IS THE SUBUNIT OF 674 00:30:19,606 --> 00:30:21,408 PROTEIN KINASE A. 675 00:30:21,408 --> 00:30:23,077 ALL THE MODEL SYSTEMS TESTED DO 676 00:30:23,077 --> 00:30:25,012 THEY HAVE THE FUSION TRANSCRIPT, 677 00:30:25,012 --> 00:30:27,181 DO THEY HAVE THE FUSION PROTEIN. 678 00:30:27,181 --> 00:30:29,550 WE ALSO LOOK AT ALL THE CHANGES 679 00:30:29,550 --> 00:30:31,885 AND TRANSCRIPTS THAT OCCUR. 680 00:30:31,885 --> 00:30:33,887 ALL THE ONES THAT GO UP. 681 00:30:33,887 --> 00:30:34,855 THERE'S FULL CHANGE GREATER THAN 682 00:30:34,855 --> 00:30:36,690 ZERO AND ALL THE ONES THAT GO 683 00:30:36,690 --> 00:30:38,592 DOWN, HOW DO THEY COMPARE TO THE 684 00:30:38,592 --> 00:30:42,262 CHANGES YOU SEE IN PATIENT 685 00:30:42,262 --> 00:30:42,496 TISSUE. 686 00:30:42,496 --> 00:30:45,532 AND WE'LL HAVE CLOSE 687 00:30:45,532 --> 00:30:46,166 RECAPITULATION AND CORRELATION 688 00:30:46,166 --> 00:30:48,535 HERE. 689 00:30:48,535 --> 00:30:52,005 SO, WHAT ARE THE KINDS OF 690 00:30:52,005 --> 00:30:52,306 STRATEGIES? 691 00:30:52,306 --> 00:30:56,043 FIRST ARE COMPOUNDS RELATIVE TO 692 00:30:56,043 --> 00:30:57,077 FIBROLAMELLAR. 693 00:30:57,077 --> 00:30:59,646 WE TOOK ALL THE COMPOUNDS WE'VE 694 00:30:59,646 --> 00:31:03,050 SEEN IN THE CLINIC AND SHOW NO 695 00:31:03,050 --> 00:31:05,552 DIFFERENCE IN THE RESPONSE OF 696 00:31:05,552 --> 00:31:10,257 THE PATIENT-DERIVED XENOGRAPHS 697 00:31:10,257 --> 00:31:15,129 FROM HEPATOCYTES AND NO 698 00:31:15,129 --> 00:31:17,531 DIFFERENCE FROM THE NORMAL 699 00:31:17,531 --> 00:31:17,798 PATIENTS. 700 00:31:17,798 --> 00:31:21,435 WE ALSO TRIED TUMORS GROWING IN 701 00:31:21,435 --> 00:31:21,635 MICE. 702 00:31:21,635 --> 00:31:28,475 THERE'S NO DRUGS FOR 703 00:31:28,475 --> 00:31:29,143 FIBROLAMELLAR TUMORS LIVING IN 704 00:31:29,143 --> 00:31:32,846 MICE AND WE ASKED WHAT WAS THE 705 00:31:32,846 --> 00:31:35,082 SURVIVAL OF THE CELLS AFTER 706 00:31:35,082 --> 00:31:35,349 TREATMENT? 707 00:31:35,349 --> 00:31:37,184 WE COULDN'T FIND ANY COMPOUNDED 708 00:31:37,184 --> 00:31:40,521 USE SHOWING ANY EFFICACY IN 709 00:31:40,521 --> 00:31:40,888 FIBROLAMELLAR. 710 00:31:40,888 --> 00:31:42,256 WE SAID WHAT IF WE TAKE A 711 00:31:42,256 --> 00:31:45,058 PRECISION MEDICINE APPROACH AND 712 00:31:45,058 --> 00:31:49,029 THOSE TARGETED TO FIBROLAMELLAR. 713 00:31:49,029 --> 00:31:53,534 I TOLD YOU THERE'S A BIG ORANGE 714 00:31:53,534 --> 00:31:55,736 DOMAIN HERE IS FROM PROTEIN 715 00:31:55,736 --> 00:31:56,770 KINASE A. 716 00:31:56,770 --> 00:31:58,439 WHAT IF WE USE DRUGS THAT 717 00:31:58,439 --> 00:32:00,707 INHIBIT PROTEIN KINASE A. 718 00:32:00,707 --> 00:32:05,145 WE USAGE ENTS KNOWN TO INHIBIT 719 00:32:05,145 --> 00:32:07,347 THIS AND THEY SHOWED LITTLE 720 00:32:07,347 --> 00:32:08,982 THROUGHPUT WINDOW BETWEEN 721 00:32:08,982 --> 00:32:13,620 DAMAGING THE FIBROLAMELLAR CELLS 722 00:32:13,620 --> 00:32:18,459 AND THE HEPATOCYTES. 723 00:32:18,459 --> 00:32:21,829 SO IT'S ESSENTIAL FOR SO MANY 724 00:32:21,829 --> 00:32:24,898 CELLS EVEN NORMAL CELLS ARE 725 00:32:24,898 --> 00:32:27,601 DAMAGED WHEN YOU KILL IT. 726 00:32:27,601 --> 00:32:29,403 WE HAVE ALL THE CHANGES IN THE 727 00:32:29,403 --> 00:32:30,771 TRANSCRIPTOME AND PROTEOME. 728 00:32:30,771 --> 00:32:31,839 MAYBE THEY CAN SUGGEST TO US 729 00:32:31,839 --> 00:32:34,975 SOME TARGETS. 730 00:32:34,975 --> 00:32:38,512 FOR EXAMPLE, THE KINASE A 731 00:32:38,512 --> 00:32:40,113 INCREASED. 732 00:32:40,113 --> 00:32:43,150 WHEN YOU USE INHIBITERS, THEY 733 00:32:43,150 --> 00:32:47,654 HAD NO EFFECT IN FIBROLAMELLAR 734 00:32:47,654 --> 00:32:51,291 COMPARED TO THE HEPATOCYTES. 735 00:32:51,291 --> 00:32:54,761 THE TRANSCRIPTOME SHOWED THE AGF 736 00:32:54,761 --> 00:32:56,864 PATHWAY US UP AND USED DRUGS 737 00:32:56,864 --> 00:32:59,566 AGAINST THIS AND THERE WAS NO 738 00:32:59,566 --> 00:33:01,535 CLEAR THERAPEUTIC WINDOW. 739 00:33:01,535 --> 00:33:11,378 AND THE GLUTAMATE PATHWAY IS IT 740 00:33:11,378 --> 00:33:13,146 THERE WAS NO PRIMARY EFFECT TO 741 00:33:13,146 --> 00:33:15,382 THE BLACK COMPARED TO 742 00:33:15,382 --> 00:33:23,056 PATIENT-DERIVED XENOGRAPHS. 743 00:33:23,056 --> 00:33:25,559 A LOT OF THE PATHWAYS AND WE 744 00:33:25,559 --> 00:33:29,530 USED INHIBITERS AND NONE OF THEM 745 00:33:29,530 --> 00:33:30,831 PREFERENTIALLY EFFECTED THE 746 00:33:30,831 --> 00:33:34,868 CELLS COMPARED TO THE PRIMARY 747 00:33:34,868 --> 00:33:36,870 HEPATOCYTES IN BLUE WHETHER YOU 748 00:33:36,870 --> 00:33:37,604 DISASSOCIATED THEM FROM THE 749 00:33:37,604 --> 00:33:39,740 TUMOR IN A DISH OR FOLLOWED THEM 750 00:33:39,740 --> 00:33:41,341 IN MICE AND TRIED TREATING THE 751 00:33:41,341 --> 00:33:41,608 MICE. 752 00:33:41,608 --> 00:33:46,146 NONE AFFECTED THE TUMOR GROWTH. 753 00:33:46,146 --> 00:33:52,953 SO, WE SAW IT RELEVANT TO THE 754 00:33:52,953 --> 00:33:56,890 BIOLOGY OF FIBROLAMELLAR DIDN'T 755 00:33:56,890 --> 00:33:57,090 WORK. 756 00:33:57,090 --> 00:33:59,993 YOUR DNA IS ENCODED BY A, T, C 757 00:33:59,993 --> 00:34:01,762 AND G. 758 00:34:01,762 --> 00:34:03,864 EVERY A COMPLIMENTS BY LETTER T 759 00:34:03,864 --> 00:34:08,268 AND G BY A C. 760 00:34:08,268 --> 00:34:14,441 AND IN THE RNA IT'S SIMILAR A, 761 00:34:14,441 --> 00:34:19,780 U, G AND C AND IF YOU COME UP 762 00:34:19,780 --> 00:34:23,550 WITH A COMPLIMENTARY PAIR TO THE 763 00:34:23,550 --> 00:34:26,486 DNA AND INSTEAD OF BINDS IT'S 764 00:34:26,486 --> 00:34:32,392 RAN BY THE RIBOSOME AND YOU CAN 765 00:34:32,392 --> 00:34:41,134 BLOCK THE SYNTHESIS. 766 00:34:41,134 --> 00:34:44,738 ACROSS THE JUNCTION ARE THE TWO 767 00:34:44,738 --> 00:34:49,610 GENES, WHERE THEY FUSE TOGETHER. 768 00:34:49,610 --> 00:34:52,913 SO THEY GOT EVERY POSSIBLE 769 00:34:52,913 --> 00:34:53,580 SPREAD BECAUSE ALL THE EARLIER 770 00:34:53,580 --> 00:34:55,716 WORK I SHOWED YOU, I SHOWED IF 771 00:34:55,716 --> 00:34:57,551 YOU PUT THIS FUSION GENE IN THE 772 00:34:57,551 --> 00:35:01,254 CHIMERA AND GET THE TUMOR, IT'S 773 00:35:01,254 --> 00:35:04,024 POSSIBLE JUST TRIGGERING IT IT'S 774 00:35:04,024 --> 00:35:08,261 NOT NEEDED ANYMORE. 775 00:35:08,261 --> 00:35:11,198 IS IT CONTINUING TO DRIVE THE 776 00:35:11,198 --> 00:35:11,398 TUMOR? 777 00:35:11,398 --> 00:35:12,432 OTHERWISE IT'S NOT A USEFUL 778 00:35:12,432 --> 00:35:13,100 THERAPEUTIC TARGET. 779 00:35:13,100 --> 00:35:15,869 IF YOU GET RID OF IT, DO THEY 780 00:35:15,869 --> 00:35:16,970 CONTINUE TO GROW? 781 00:35:16,970 --> 00:35:19,139 IF YOU LIMIT TO DRIVER, DO THE 782 00:35:19,139 --> 00:35:19,640 CELLS NORMALIZE OR DIE 783 00:35:19,640 --> 00:35:28,415 >> IF THEY FORMALIZE FOR THE 784 00:35:28,415 --> 00:35:29,516 REST OF THE LIFE OF THE PATIENT 785 00:35:29,516 --> 00:35:32,252 YOU HAVE TO GIVE THE DRUG TO 786 00:35:32,252 --> 00:35:37,424 CREATE THE CHIMERA AND WITH 787 00:35:37,424 --> 00:35:39,126 LONG-TERM TREATMENT THEY CAN 788 00:35:39,126 --> 00:35:43,497 FIND WAYS TO ESCAPE FROM IT. 789 00:35:43,497 --> 00:35:46,233 HS RNA WOULD GET RID OF THE 790 00:35:46,233 --> 00:35:48,201 FUSION PROTEIN BUT NOT AFFECT 791 00:35:48,201 --> 00:35:49,469 THE WILD TYPE PROTEIN. 792 00:35:49,469 --> 00:35:53,173 THEN IF YOU HAD TUMORS GROWING 793 00:35:53,173 --> 00:35:56,176 IN MICE YOU THEN INTRODUCED THIS 794 00:35:56,176 --> 00:35:58,679 SH RNA THE TUMORS WOULD STOP 795 00:35:58,679 --> 00:35:58,945 GROWING. 796 00:35:58,945 --> 00:36:02,149 HERE'S THE TUMOR GROWING AND 797 00:36:02,149 --> 00:36:02,916 THEY ACTUALLY STOP GROWING. 798 00:36:02,916 --> 00:36:05,485 IN FACT WHEN THEY STOP THEY FADE 799 00:36:05,485 --> 00:36:05,819 AWAY. 800 00:36:05,819 --> 00:36:07,487 THIS TELLS US IT'S NOT ONLY 801 00:36:07,487 --> 00:36:08,855 INVOLVED IN TRIGGERING THE TUMOR 802 00:36:08,855 --> 00:36:09,456 BUT CONTINUING TO DRIVE THE 803 00:36:09,456 --> 00:36:13,093 TUMOR. 804 00:36:13,093 --> 00:36:15,362 NOT ONLY DRIVE IT BUT WHEN YOU 805 00:36:15,362 --> 00:36:20,834 TAKE IT AWAY THEY DIE AND FADE 806 00:36:20,834 --> 00:36:21,068 AWAY. 807 00:36:21,068 --> 00:36:24,371 WE'VE BEEN DELIVERING WITH A 808 00:36:24,371 --> 00:36:26,106 SILENCING RNA AND OPTIMIZING 809 00:36:26,106 --> 00:36:28,141 DELIVERY TO THE CELL AND ONE 810 00:36:28,141 --> 00:36:28,742 THERAPEUTIC APPROACH SHOWING 811 00:36:28,742 --> 00:36:28,975 PROMISE. 812 00:36:28,975 --> 00:36:34,247 WHAT'S THE SECOND APPROACH? 813 00:36:34,247 --> 00:36:39,119 COME UP WITH DEGRADER OF THE OPT 814 00:36:39,119 --> 00:36:40,353 GENIC PROTEIN. 815 00:36:40,353 --> 00:36:42,222 IF YOU HAVE SOMETHING THAT BINDS 816 00:36:42,222 --> 00:36:44,191 TO GET RID OF YOU CAN TAKE WHAT 817 00:36:44,191 --> 00:36:45,559 BINDS TO THE PROTEIN YOU WANT TO 818 00:36:45,559 --> 00:36:48,195 GET RID OF AND LINK IT TO AN EN 819 00:36:48,195 --> 00:36:51,631 TIME OR PUT TAGS ON IT AND SEND 820 00:36:51,631 --> 00:36:57,137 IT TO THE GARBAGE DISPOSAL THE 821 00:36:57,137 --> 00:36:57,537 PROTEASOME. 822 00:36:57,537 --> 00:37:02,709 THE TAG IS UBIQUITIN AND IT THE 823 00:37:02,709 --> 00:37:06,246 BIND TO OUR FUSION PROTEIN. 824 00:37:06,246 --> 00:37:07,814 WE SCREEN THROUGH 500,000 825 00:37:07,814 --> 00:37:10,150 COMPOUNDS AND YOU HAVE 14 826 00:37:10,150 --> 00:37:19,159 INHIBITED BELOW 100 NANO MOLE 827 00:37:19,159 --> 00:37:21,027 AND THE FUSION PROTEIN THAT 828 00:37:21,027 --> 00:37:22,295 INHIBITED AT THE SAME INHIBITED 829 00:37:22,295 --> 00:37:23,196 THE WILD TYPE PROTEIN. 830 00:37:23,196 --> 00:37:24,464 THAT'S A PROBLEM. 831 00:37:24,464 --> 00:37:27,534 I SAID EARLIER THE WILD TYPE 832 00:37:27,534 --> 00:37:28,835 PROP 833 00:37:28,835 --> 00:37:29,970 PROTEIN IS IMPORTANT FOR THE 834 00:37:29,970 --> 00:37:31,037 HEALTH OF THE CELL SO CAN WE 835 00:37:31,037 --> 00:37:32,205 FIND A WAY AROUND IT 836 00:37:32,205 --> 00:37:35,275 ? 837 00:37:35,275 --> 00:37:38,545 WE NOTICED THE KINASE IS TITLELY 838 00:37:38,545 --> 00:37:38,879 FOLDED. 839 00:37:38,879 --> 00:37:48,622 BECAUSE IT'S TITLELY -- TIGHTLY 840 00:37:48,622 --> 00:37:50,056 FOLDS IT'S BOUND TO THE CELL AND 841 00:37:50,056 --> 00:37:51,792 THIS FUSION DOMAIN IS FLEXIBLE 842 00:37:51,792 --> 00:37:54,661 MAKING IT A GOOD SUBSTRATE AND 843 00:37:54,661 --> 00:37:56,029 HAS THE POTENTIAL TO BE DEGRADED 844 00:37:56,029 --> 00:38:00,300 AND BEYOND THAT HAS MANY AMINO 845 00:38:00,300 --> 00:38:03,703 ACID LYSINES AND THAT'S AMINO 846 00:38:03,703 --> 00:38:09,176 ACID THAT GETS UBIQUITIN ADDED 847 00:38:09,176 --> 00:38:11,344 ON TO TARGET THE PROTEASOME. 848 00:38:11,344 --> 00:38:13,079 IF IT BINDS TO THE WILD TYPE AND 849 00:38:13,079 --> 00:38:16,049 FUSION TOGETHER, IF WE CAN 850 00:38:16,049 --> 00:38:19,686 COMBINED IT WITH AN ENZYME 851 00:38:19,686 --> 00:38:30,230 CALLED E3 LISASE WE CAN DEGRADE 852 00:38:30,864 --> 00:38:30,964 IT. 853 00:38:30,964 --> 00:38:36,937 WE FOUND WE SLIGHTLY DEGRADED IT 854 00:38:36,937 --> 00:38:47,180 OVER THE WILD TYPE MAHSA DID 855 00:38:47,180 --> 00:38:48,582 THIS AND IF YOU'RE TUMOR IS 856 00:38:48,582 --> 00:38:51,418 GROWING IN MICE YOU INTRODUCE 857 00:38:51,418 --> 00:38:53,119 AND THE TUMOR WILL STOP GROWING 858 00:38:53,119 --> 00:38:55,622 AND FADE AWAY. 859 00:38:55,622 --> 00:38:56,890 THESE ARE TWO POTENTIAL 860 00:38:56,890 --> 00:38:57,891 THERAPEUTIC APPROACHES AND 861 00:38:57,891 --> 00:38:59,593 ANTISENSE AND DEGRADER. 862 00:38:59,593 --> 00:39:01,828 THESE ARE ALL UNDERGOING 863 00:39:01,828 --> 00:39:02,662 DEVELOPMENT BUT THE THING IS 864 00:39:02,662 --> 00:39:03,797 PEOPLE ARE DYING NOW AND 865 00:39:03,797 --> 00:39:05,632 PATIENTS ARE WORKING IN THE LAB 866 00:39:05,632 --> 00:39:08,368 AND SICK AND AROUND THE WORLD 867 00:39:08,368 --> 00:39:08,735 ARE SICK. 868 00:39:08,735 --> 00:39:09,703 THE QUESTION IS WHAT IS 869 00:39:09,703 --> 00:39:16,943 IMPORTANT TO THE CLINIC NOW? 870 00:39:16,943 --> 00:39:17,444 -- 871 00:39:17,444 --> 00:39:17,978 >> HELLO? 872 00:39:17,978 --> 00:39:18,511 >> YES. 873 00:39:18,511 --> 00:39:20,614 CAN YOU HEAR ME? 874 00:39:20,614 --> 00:39:21,948 >> I THINK YOU'RE OKAY. 875 00:39:21,948 --> 00:39:29,556 WIN MAY BE DOING SOMETHING ELSE. 876 00:39:29,556 --> 00:39:35,729 >> WE TOOK THE DRUGS THAT PAST 877 00:39:35,729 --> 00:39:39,032 PHASE 1 CLINICAL TESTS AND SAW 878 00:39:39,032 --> 00:39:41,001 WHICH HAS EFFECT AT ALL OR 879 00:39:41,001 --> 00:39:45,038 SHOWED A SLIGHT ENCOURAGING SIGN 880 00:39:45,038 --> 00:39:49,342 WE TESTS FROM 10 NANOMOLE TO 881 00:39:49,342 --> 00:39:50,610 MICROMOLE AGAINST THE PATIENT 882 00:39:50,610 --> 00:39:57,050 DERIVED XENOGRAPHS OR ADJACENT 883 00:39:57,050 --> 00:40:01,288 TISSUE. 884 00:40:01,288 --> 00:40:03,790 SOME WORKED WELL AGAINST THE 885 00:40:03,790 --> 00:40:05,458 DECH DEF 886 00:40:09,296 --> 00:40:16,102 THE XENO GRAPH AND IT'S AN 887 00:40:16,102 --> 00:40:16,369 INHIBITER. 888 00:40:16,369 --> 00:40:20,006 WHEN CELLS DIVIDE THEY TAKE A 889 00:40:20,006 --> 00:40:30,417 DOUBLE HELIX AND UNWIND. 890 00:40:31,284 --> 00:40:36,656 AND FIBROLAMELLAR IS A SLOW 891 00:40:36,656 --> 00:40:47,133 GROWING CELL AND FOUND PA 892 00:40:48,168 --> 00:40:49,569 PANOBINOSTAT WORKS AND THERE 893 00:40:49,569 --> 00:40:53,773 WERE INHIBITORS OF THE MOLECULE 894 00:40:53,773 --> 00:40:56,176 THAT PROTECTS THE CELL FROM 895 00:40:56,176 --> 00:40:58,244 UNDERGOING CELL DEATH. 896 00:40:58,244 --> 00:40:59,546 I GOT WORRIED. 897 00:40:59,546 --> 00:41:01,081 NONE OF THESE WERE EXPECTED. 898 00:41:01,081 --> 00:41:03,016 WE WERE TAKING THE TUMORS FROM 899 00:41:03,016 --> 00:41:04,951 PATIENTS AND PLANTING THEM IN 900 00:41:04,951 --> 00:41:06,653 MICE AND SOMETIMES IT TOOK NINE 901 00:41:06,653 --> 00:41:08,655 MONTHS FOR THE TUMOR TO GROW. 902 00:41:08,655 --> 00:41:11,224 WHAT IF OUT OF A BILLION CELLS 903 00:41:11,224 --> 00:41:18,631 599, 9 99 ONE GREW UP. 904 00:41:18,631 --> 00:41:21,034 AND IT REPRESENTED THE NORMAL 905 00:41:21,034 --> 00:41:22,736 TUMORS IN THE PATIENT. 906 00:41:22,736 --> 00:41:25,005 WHEN WE GET RESULTS LIKE THIS, 907 00:41:25,005 --> 00:41:27,040 DOES IT REPORT ON THE BEHAVIOR 908 00:41:27,040 --> 00:41:29,109 OF TUMORS IN THE PATIENTS? 909 00:41:29,109 --> 00:41:32,145 WE SWITCHED NOW TO GET TUMORS 910 00:41:32,145 --> 00:41:36,282 DIRECTLY TO PATIENTS AND 911 00:41:36,282 --> 00:41:37,751 DISASSOCIATE THEM AND SCREEN 912 00:41:37,751 --> 00:41:39,152 THEM AGAINST THE DRUGS. 913 00:41:39,152 --> 00:41:41,554 THE SAMPLES FROM THE PATIENTS 914 00:41:41,554 --> 00:41:44,591 SHOWED THE SAME RESPONSE 915 00:41:44,591 --> 00:41:44,891 PROFILE. 916 00:41:44,891 --> 00:41:49,129 SO WE USED SAMPLE FROM A VARIETY 917 00:41:49,129 --> 00:41:49,562 OF PATIENTS HERE. 918 00:41:49,562 --> 00:41:52,232 ALL THE PATIENTS RESPONDED IN 919 00:41:52,232 --> 00:41:53,533 CONCENTRATIONS MUCH LOWER THAN 920 00:41:53,533 --> 00:41:55,802 THE CONCENTRATIONS HERE IN BLACK 921 00:41:55,802 --> 00:42:00,740 THE PRIMARY HUMAN HEPATOCYTES 922 00:42:00,740 --> 00:42:04,010 AND HERE SOME PATIENTS WERE 923 00:42:04,010 --> 00:42:05,545 SENSITIVE, SOME WERE 924 00:42:05,545 --> 00:42:07,213 HYPERSENSITIVE. 925 00:42:07,213 --> 00:42:10,950 WE WERE WONDERING, WHY ARE THERE 926 00:42:10,950 --> 00:42:11,317 DIFFERENCES? 927 00:42:11,317 --> 00:42:15,155 WHY ARE SOME SENSITIVE AND ALL 928 00:42:15,155 --> 00:42:16,723 THE CHANGES IN THE GENE 929 00:42:16,723 --> 00:42:17,957 EXPRESSION AND PROTEINS SEEM TO 930 00:42:17,957 --> 00:42:23,563 BE THE SAME PATIENT TO PATIENT. 931 00:42:23,563 --> 00:42:26,433 AND WHAT SURGEONS HAVE TO DO IS 932 00:42:26,433 --> 00:42:31,137 BURN AROUND THE ENTIRE TUMORS TO 933 00:42:31,137 --> 00:42:32,172 INCREASE THE BLOOD FLOW WHEN 934 00:42:32,172 --> 00:42:35,175 WHEN THEY RESET THE TUMOR 935 00:42:35,175 --> 00:42:36,209 THERE'S NOT A LOT OF BLEEDING 936 00:42:36,209 --> 00:42:40,113 AND THE TUMORS HAVE REDUCED 937 00:42:40,113 --> 00:42:45,151 BLOOD FLOW AND OXYGEN ALONG WITH 938 00:42:45,151 --> 00:42:49,556 BEING TREATMENTS AND WHEN WE 939 00:42:49,556 --> 00:42:50,590 DISASSOCIATE A TUMOR MAYBE 940 00:42:50,590 --> 00:42:53,026 BECAUSE OF LOSS OF OXYGEN OR HOW 941 00:42:53,026 --> 00:42:56,262 WE DIGESTED IT, EVERY SINGLE 942 00:42:56,262 --> 00:42:56,896 SAMPLE WAS DIFFERENT. 943 00:42:56,896 --> 00:42:59,032 MAYBE SOMETHING IN OUR 944 00:42:59,032 --> 00:42:59,332 TECHNIQUE? 945 00:42:59,332 --> 00:43:01,534 THERE'S QUITE A FEW PATIENTS HAD 946 00:43:01,534 --> 00:43:05,538 SURGERIES THAT WERE A FEW YEARS 947 00:43:05,538 --> 00:43:05,972 A PART. 948 00:43:05,972 --> 00:43:08,141 AND SOME WERE DONE THREE YEARS A 949 00:43:08,141 --> 00:43:10,910 PART AND WITHIN THE SAME PATIENT 950 00:43:10,910 --> 00:43:13,546 THE RESPONSE EARLIER IS THE 951 00:43:13,546 --> 00:43:16,249 PRIMARY TUMOR HERE'S THE 952 00:43:16,249 --> 00:43:20,453 RESPONSE OF THREE OF THE 953 00:43:20,453 --> 00:43:21,354 PATIENTS METASTASES AND SAME FOR 954 00:43:21,354 --> 00:43:22,956 ALL DRUGS TESTED. 955 00:43:22,956 --> 00:43:25,091 WITHIN A SINGLE PATIENT THE DRUG 956 00:43:25,091 --> 00:43:28,128 RESPONSE PROFILE WAS ALWAYS THE 957 00:43:28,128 --> 00:43:29,496 SAME IT'S TELLING US THE 958 00:43:29,496 --> 00:43:32,765 DIFFERENCE WE'RE SEEING IS NOT A 959 00:43:32,765 --> 00:43:38,171 DIFFERENCE IN OUR PROTOCOL BUT A 960 00:43:38,171 --> 00:43:38,805 DIFFERENCE IN THE RESPONSE FROM 961 00:43:38,805 --> 00:43:42,475 PATIENT TO PATIENT. 962 00:43:42,475 --> 00:43:44,444 AND I MENTIONED ONE OF THE DRUGS 963 00:43:44,444 --> 00:43:46,813 THAT WORKED REALLY WELL WAS A 964 00:43:46,813 --> 00:43:50,783 DRUG THAT INHIBITED THE 965 00:43:50,783 --> 00:43:52,318 ANTI-CELL DEATH PATHWAY AND WE 966 00:43:52,318 --> 00:43:54,220 FOUND BETWEEN THE DIFFERENT 967 00:43:54,220 --> 00:43:55,455 PATIENTS THE ONES SENSITIVE AND 968 00:43:55,455 --> 00:43:58,491 VERY SENSITIVE, THERE WERE 969 00:43:58,491 --> 00:44:00,226 DIFFERENCES IN EXPRESSION OF THE 970 00:44:00,226 --> 00:44:02,762 ANTI-CELL DEATH PATHWAY. 971 00:44:02,762 --> 00:44:03,830 WE ASKED WHAT HAPPENS IF WE 972 00:44:03,830 --> 00:44:04,964 COMBINE TOGETHER WITH A CELL 973 00:44:04,964 --> 00:44:08,801 THAT BLOCKS THE PATHWAY AND 974 00:44:08,801 --> 00:44:11,237 DRUGS WE'RE TREATING? 975 00:44:11,237 --> 00:44:15,508 IN BLUE WAS THE PATIENT LEAST 976 00:44:15,508 --> 00:44:15,775 SENSITIVE. 977 00:44:15,775 --> 00:44:18,344 AND WHEN GOT SAMPLES DIRECTLY 978 00:44:18,344 --> 00:44:20,013 FROM THE PATIENTS THIS IS DONE 979 00:44:20,013 --> 00:44:23,650 THROUGH A LARGE ROBOTIC SYSTEM 980 00:44:23,650 --> 00:44:27,153 WE BLOCKED B CELL EXCEL. 981 00:44:27,153 --> 00:44:29,422 WE FOUND THE MORE WE INHIBITED 982 00:44:29,422 --> 00:44:30,690 THE MORE SENSITIVE AND THE 983 00:44:30,690 --> 00:44:34,127 SENSITIVE WENT DOWN TO SINGLE 984 00:44:34,127 --> 00:44:37,530 DIGIT NANOMOLE. 985 00:44:37,530 --> 00:44:40,900 THE DIFFERENCES WERE DUE TO THE 986 00:44:40,900 --> 00:44:42,502 APOPTOTIC PROTEIN. 987 00:44:42,502 --> 00:44:43,503 OTHERWISE THE PATIENT RESPONSE 988 00:44:43,503 --> 00:44:44,737 WAS PRETTY MUCH THE SAME PATIENT 989 00:44:44,737 --> 00:44:47,674 TO PATIENT. 990 00:44:47,674 --> 00:44:52,445 NOW, A PROBLEM USING NAVIHOCLAX 991 00:44:52,445 --> 00:44:57,150 IT BLOCKS AND ADVERSELY AFFECTS 992 00:44:57,150 --> 00:45:07,594 THE PLATELETS AND CREATES 993 00:45:09,596 --> 00:45:11,197 THROMBOCYTOPENIA AND THEY PUT IN 994 00:45:11,197 --> 00:45:21,741 LIGASES AND DESTROYED IT AND IT 995 00:45:23,076 --> 00:45:27,046 ONLY AFFECTED B CELL EXCEL AND 996 00:45:27,046 --> 00:45:33,152 USED THE LIGASE THAT AFFECT THE 997 00:45:33,152 --> 00:45:33,419 PLATELETS. 998 00:45:33,419 --> 00:45:36,256 WE FOUND WITHIN 24 HOURS OF 999 00:45:36,256 --> 00:45:40,426 TREATMENT IN A MOUSE WE CAN 1000 00:45:40,426 --> 00:45:45,164 ELIMINATE THE ABOUT BCL-XL AND 1001 00:45:45,164 --> 00:45:45,965 THE PLATELETS INCREASED. 1002 00:45:45,965 --> 00:45:49,302 THERE WERE NO CHANGES IN 1003 00:45:49,302 --> 00:45:54,307 BILIRUBIN OR AFFECT ON LIVER 1004 00:45:54,307 --> 00:45:54,741 ENZ 1005 00:45:54,741 --> 00:45:55,675 ENZYMES. 1006 00:45:55,675 --> 00:46:01,614 IT THEY INHIBITED IT WELL. 1007 00:46:01,614 --> 00:46:03,416 IF WE JUST HAVE THIS TREATMENT 1008 00:46:03,416 --> 00:46:05,785 STRATEGY, FIVE DAYS ON, TWO DAYS 1009 00:46:05,785 --> 00:46:07,253 OFF, FIVE DAYS ON. 1010 00:46:07,253 --> 00:46:10,757 THERE'S THREE ROUNDS OF TWO 1011 00:46:10,757 --> 00:46:11,057 TREATMENTS. 1012 00:46:11,057 --> 00:46:13,526 YOU SEE WHAT IS EFFECTIVELY 1013 00:46:13,526 --> 00:46:21,034 STABLE DISEASE. 1014 00:46:21,034 --> 00:46:22,368 NOW, IF YOU STOP TREATMENT THE 1015 00:46:22,368 --> 00:46:26,139 TUMOR DOES NOT CONTINUE TO GROW. 1016 00:46:26,139 --> 00:46:27,840 NOW IF WE ADD TO THE TREATMENT 1017 00:46:27,840 --> 00:46:30,476 OF THE DEGRADER, NOT ONLY DOES 1018 00:46:30,476 --> 00:46:31,744 THE TUMOR GROW AWAY BUT YOU STOP 1019 00:46:31,744 --> 00:46:33,246 TREATMENT AND THE TUMOR DOES NOT 1020 00:46:33,246 --> 00:46:37,350 COME BACK. 1021 00:46:37,350 --> 00:46:39,819 IT'S BEING TESTED AS A MODEL 1022 00:46:39,819 --> 00:46:43,156 THERAPY TO GO IN OUR PATIENT 1023 00:46:43,156 --> 00:46:44,424 REGISTRY WE FOUND NINE PATIENTS 1024 00:46:44,424 --> 00:46:46,225 WHO RECEIVED IT AND THEY FOUND 1025 00:46:46,225 --> 00:46:48,895 THEIR TUMOR STABILIZED OR 1026 00:46:48,895 --> 00:46:49,629 SLIGHTLY DECREASED JUST AS SEEN 1027 00:46:49,629 --> 00:46:52,632 IN THE MICE. 1028 00:46:52,632 --> 00:46:58,538 A STUDY COMBINING THE TWO IS 1029 00:46:58,538 --> 00:46:59,872 INVESTIGATING AND OPENING A 1030 00:46:59,872 --> 00:47:01,607 CLINICAL TRIAL AND THE FIRST IS 1031 00:47:01,607 --> 00:47:06,279 STARTING SOON. 1032 00:47:06,279 --> 00:47:08,881 SHOULD THE DRUGS BE WORKING? 1033 00:47:08,881 --> 00:47:10,950 WOULD I GIVE THIS TO MY OWN KID? 1034 00:47:10,950 --> 00:47:17,523 THIS IS NOT PREDICTED TO WORK. 1035 00:47:17,523 --> 00:47:20,860 WE EXAMINED WHAT IT IS AND IT'S 1036 00:47:20,860 --> 00:47:23,596 AN ACTIVE METABOLITE AND ONCE 1037 00:47:23,596 --> 00:47:26,132 IT'S IN THE LIVER CELLS THEY PUT 1038 00:47:26,132 --> 00:47:29,769 ON A SUGAR GROUP WHICH ALLOWS IT 1039 00:47:29,769 --> 00:47:33,539 TO BE EXPORTED INTO THE BILE AND 1040 00:47:33,539 --> 00:47:35,942 THE BODY GETS RID OF IT. 1041 00:47:35,942 --> 00:47:37,877 THE FUSION GENE, THE CHIMERIC 1042 00:47:37,877 --> 00:47:39,846 WHEN IT'S INCREASED IN 1043 00:47:39,846 --> 00:47:41,547 EXPRESSION, IT ACTUALLY 1044 00:47:41,547 --> 00:47:45,551 REGULATES THE EXPRESSION AND 1045 00:47:45,551 --> 00:47:47,220 DOWN REGULATED ABOUT 50 FOLD. 1046 00:47:47,220 --> 00:47:48,321 BECAUSE IT'S DOWN REGULATED SO 1047 00:47:48,321 --> 00:47:49,322 MUCH THE CELLS NO LONGER HAVE 1048 00:47:49,322 --> 00:47:51,924 THE ABILITY TO PUT A SUGAR GROUP 1049 00:47:51,924 --> 00:47:54,093 ON AND IT BUILDS INSIDE THE 1050 00:47:54,093 --> 00:47:54,293 CELLS. 1051 00:47:54,293 --> 00:47:58,998 WE LEAVE YOU WITH FIBROLAMELLAR 1052 00:47:58,998 --> 00:48:07,707 CARCINOMA INFUSES TO PRKC KINASE 1053 00:48:07,707 --> 00:48:10,710 A AND IT'S SUFFICIENT TO CREATE 1054 00:48:10,710 --> 00:48:21,220 IT IN THE LIVER OF MICE AND A 1055 00:48:21,521 --> 00:48:23,523 FUNCTIONAL PRECISION MEDICINE 1056 00:48:23,523 --> 00:48:25,324 SCREEN IDENTIFIES AGENTS THAT 1057 00:48:25,324 --> 00:48:28,528 SHOW EFFICACY ON CELLS 1058 00:48:28,528 --> 00:48:29,195 DISASSOCIATED FROM TUMORS IN 1059 00:48:29,195 --> 00:48:31,497 MICE AND IN PATIENTS AND TUMORS 1060 00:48:31,497 --> 00:48:33,599 GROWING IN MICE AND PATIENTS. 1061 00:48:33,599 --> 00:48:36,302 THE EFFICACY OF THE DRUGS CAN BE 1062 00:48:36,302 --> 00:48:37,069 UNDERSTOOD FROM AN ANALYSIS OF 1063 00:48:37,069 --> 00:48:42,041 THE BIOLOGY OF THE TUMOR. 1064 00:48:42,041 --> 00:48:45,244 OFTEN IT'S NOT THE TARGET BUT 1065 00:48:45,244 --> 00:48:51,184 THE PATHWAY AND I'LL LEAVE YOU 1066 00:48:51,184 --> 00:48:52,852 WITH CHARACTERIZATION OF THE 1067 00:48:52,852 --> 00:48:54,320 CANCER, EVEN RARE CANCER CAN 1068 00:48:54,320 --> 00:48:56,456 HAVE RAPID ADVANCES THAT CAN 1069 00:48:56,456 --> 00:48:57,256 FORM ANY DISEASE. 1070 00:48:57,256 --> 00:48:59,826 PATIENTS ARE EAGER TO PARTNER 1071 00:48:59,826 --> 00:49:01,794 AND MAKING PATIENTS FULL 1072 00:49:01,794 --> 00:49:05,498 PARTNERS NOT JUST AS A SOURCE OF 1073 00:49:05,498 --> 00:49:08,601 TISSUE AND DEVELOP CURES, I WANT 1074 00:49:08,601 --> 00:49:10,970 TO THANK THE FIBROLAMELLAR 1075 00:49:10,970 --> 00:49:11,237 PATIENTS. 1076 00:49:11,237 --> 00:49:13,406 THIS IS MY DAUGHTER DESCRIBING 1077 00:49:13,406 --> 00:49:14,574 THE DISCOVERY OF THE DELETION 1078 00:49:14,574 --> 00:49:16,242 THAT LED TO THE FUSION GENE. 1079 00:49:16,242 --> 00:49:20,546 AT THIS POINT SHE'S DESCRIBING 1080 00:49:20,546 --> 00:49:22,148 PROMISING YOUNGER CANCER 1081 00:49:22,148 --> 00:49:23,416 BIOLOGISTS HOPEFULLY WILL 1082 00:49:23,416 --> 00:49:25,218 CONTINUE PURSUING THE STUDIES. 1083 00:49:25,218 --> 00:49:27,720 THIS IS JACKSON WHO WORKED ON 1084 00:49:27,720 --> 00:49:28,621 THE GENE. 1085 00:49:28,621 --> 00:49:31,691 A WONDERFUL CHEMIST WHO 1086 00:49:31,691 --> 00:49:33,092 UNFORTUNATELY PASSED AFTER HIS 1087 00:49:33,092 --> 00:49:37,530 26th BIRTHDAY AND HELPED DEVELOP 1088 00:49:37,530 --> 00:49:42,635 OUR ORGANOIDS AND TAWNEY PASSED 1089 00:49:42,635 --> 00:49:46,005 ON THEIR 21st BIRTHDAY AND WITH 1090 00:49:46,005 --> 00:49:49,609 DID INFORMATICS AND SHE PASSED 1091 00:49:49,609 --> 00:49:50,543 AROUND 25. 1092 00:49:50,543 --> 00:49:55,615 SKY IS WORK WITH STEVE. 1093 00:49:55,615 --> 00:49:56,516 CHARLOTTE PASSED THIS PAST 1094 00:49:56,516 --> 00:49:56,749 AUGUST. 1095 00:49:56,749 --> 00:49:58,551 I WANT TO THANK ALL THE MEMBERS 1096 00:49:58,551 --> 00:50:00,353 OF MY LAB. 1097 00:50:00,353 --> 00:50:02,622 THESE ARE THE CURRENT MEMBERS OF 1098 00:50:02,622 --> 00:50:06,125 MY LAB AND DEDICATED TO THE WORK 1099 00:50:06,125 --> 00:50:08,294 AND PATIENTS. 1100 00:50:08,294 --> 00:50:09,695 I'LL LEAVE THE FINAL WORD TO ONE 1101 00:50:09,695 --> 00:50:13,266 OF ME PATIENTS. 1102 00:50:13,266 --> 00:50:14,000 >> LADIES AND GENTLEMEN, THE 1103 00:50:14,000 --> 00:50:16,569 PRESIDENT OF THE UNITED STATES 1104 00:50:16,569 --> 00:50:27,113 ACCOMPANIED BY MS. ALANA SIMON. 1105 00:50:35,721 --> 00:50:38,057 >> I'M 19 YEARS OLD AND 1106 00:50:38,057 --> 00:50:39,091 CURRENTLY STUDYING COMPUTER 1107 00:50:39,091 --> 00:50:40,426 SCIENCE AT HARVARD. 1108 00:50:40,426 --> 00:50:45,264 WHEN YOU I WAS 12 YEARS OLD I 1109 00:50:45,264 --> 00:50:51,170 WAS DIAGNOSED WITH 1110 00:50:51,170 --> 00:50:58,444 HEPATOCELLULAR FIBE RA -- FIB 1111 00:50:58,444 --> 00:51:03,649 FIBROLAMELLAR CARCINOMA AND I 1112 00:51:03,649 --> 00:51:05,551 EXAMINED A PATIENT GROUP WHICH 1113 00:51:05,551 --> 00:51:07,253 ALLOWED THE DISCOVERY. 1114 00:51:07,253 --> 00:51:09,255 WE'RE WORKING ON DEVELOPING THE 1115 00:51:09,255 --> 00:51:10,756 FIRST DIAGNOSTIC TESTS AND 1116 00:51:10,756 --> 00:51:13,492 TREATMENTS FOR FIBROLAMELLAR. 1117 00:51:13,492 --> 00:51:14,927 LAST YEAR I MET THE PRESIDENT 1118 00:51:14,927 --> 00:51:16,462 AND GOT TO DISCUSS MY RESEARCH 1119 00:51:16,462 --> 00:51:16,929 WITH HIM. 1120 00:51:16,929 --> 00:51:21,267 IT WAS SUCH AN HONOR TO MEET HIM 1121 00:51:21,267 --> 00:51:25,571 THEN SO IT'S WITH GREAT HONOR I 1122 00:51:25,571 --> 00:51:26,238 INTRODUCE THE PRESIDENT TO YOU 1123 00:51:26,238 --> 00:51:32,745 TODAY. 1124 00:51:32,745 --> 00:51:34,480 >> ANYWAY, I WANT TO THANK THE 1125 00:51:34,480 --> 00:51:36,215 PATIENTS AND THEIR FAMILIES AND 1126 00:51:36,215 --> 00:51:36,882 ALL OF YOU FOR YOUR ATTENTION. 1127 00:51:36,882 --> 00:51:43,055 THANK YOU. 1128 00:51:43,055 --> 00:51:46,225 >> THANK YOU VERY MUCH, SANDY 1129 00:51:46,225 --> 00:51:51,330 FOR THIS EXTRAORDINARILY 1130 00:51:51,330 --> 00:51:52,431 EXCITING, PROMISING AND 1131 00:51:52,431 --> 00:51:55,701 BEAUTIFUL EXAMPLE AND THE NEED 1132 00:51:55,701 --> 00:51:58,304 FOR BRIDGES NOT ONLY WITHIN THE 1133 00:51:58,304 --> 00:52:00,506 SCIENCES BUT OF COURSE WITHIN 1134 00:52:00,506 --> 00:52:04,043 THE PATIENTS AND ALMOST ALL 1135 00:52:04,043 --> 00:52:07,046 DISEAS 1136 00:52:07,046 --> 00:52:07,947 DISEASES WITH THE GREATEST 1137 00:52:07,947 --> 00:52:08,914 INVESTMENT AND INTEREST. 1138 00:52:08,914 --> 00:52:13,019 WE'RE GOING TO PROCEED NOW TO 1139 00:52:13,019 --> 00:52:15,388 MARC GHANY. 1140 00:52:15,388 --> 00:52:16,489 A REMINDER TO SUBMIT YOUR 1141 00:52:16,489 --> 00:52:18,257 QUESTIONS AND WE'LL HAVE A 1142 00:52:18,257 --> 00:52:19,659 DISCUSSION AT THE END OF 1143 00:52:19,659 --> 00:52:21,394 DR. GHANY'S TALK. 1144 00:52:21,394 --> 00:52:27,733 MARC. 1145 00:52:27,733 --> 00:52:32,071 >> THAT WAS A WONDERFUL TALK, 1146 00:52:32,071 --> 00:52:32,471 SANDY. 1147 00:52:32,471 --> 00:52:42,982 THANKS FOR SETTING THE STAGE. 1148 00:52:45,017 --> 00:52:47,319 SO THAT WAS A WONDERFUL TALK AND 1149 00:52:47,319 --> 00:52:50,923 I WANTED TO EXTEND MY THANKS AND 1150 00:52:50,923 --> 00:52:54,994 GRATITUDE TO WIN FOR THE INV 1151 00:52:54,994 --> 00:52:55,928 INVITA 1152 00:52:55,928 --> 00:52:56,228 INVITATION. 1153 00:52:56,228 --> 00:52:58,097 IT'S AN AMAZING COURSE AND WIN 1154 00:52:58,097 --> 00:53:01,834 IS AN AMAZING INDIVIDUAL. 1155 00:53:01,834 --> 00:53:05,638 THIS COURSE HAS BEEN GOING ON 22 1156 00:53:05,638 --> 00:53:07,306 YEARS AND I'VE LEARNED 1157 00:53:07,306 --> 00:53:08,641 PERSONALLY A LOT FROM IT AND 1158 00:53:08,641 --> 00:53:11,010 HOPE EVERYBODY ELSE PROFITS FROM 1159 00:53:11,010 --> 00:53:17,516 WIN'S HARD WORK. 1160 00:53:17,516 --> 00:53:20,152 TODAY I'M GOING TO TALK A LITTLE 1161 00:53:20,152 --> 00:53:23,756 BIT ABOUT THE MORE COMMON CANCER 1162 00:53:23,756 --> 00:53:25,925 WHICH IS HEPATOCELLULAR 1163 00:53:25,925 --> 00:53:28,894 CARCINOMA AND CONFINE MY 1164 00:53:28,894 --> 00:53:31,263 COMMENTS TO THE EPIDEMIOLOGY 1165 00:53:31,263 --> 00:53:31,864 SURVEILLANCE, DIAGNOSIS AND 1166 00:53:31,864 --> 00:53:37,470 TREATMENT OF HEPATOCELLULAR 1167 00:53:37,470 --> 00:53:37,803 CARCINOMA. 1168 00:53:37,803 --> 00:53:42,041 AS YOU HEARD IT'S THE SIXTH MOST 1169 00:53:42,041 --> 00:53:45,377 COMMON AND THIRD CAUSE OF DEATH. 1170 00:53:45,377 --> 00:53:47,847 IT HAS THE HIGHEST CASE FATALITY 1171 00:53:47,847 --> 00:53:49,582 RATES AND ESSENTIALLY IT'S A 1172 00:53:49,582 --> 00:53:54,186 DEATH SENTENCE BECAUSE 50% OF 1173 00:53:54,186 --> 00:53:56,989 PATIENTS WILL BE DEAD TWO YEARS 1174 00:53:56,989 --> 00:53:58,491 AFTER DIAGNOSIS. 1175 00:53:58,491 --> 00:54:01,560 IT ACCOUNTS FOR 70% TO 85% OF 1176 00:54:01,560 --> 00:54:01,961 CASES. 1177 00:54:01,961 --> 00:54:12,505 THE INS INCIDENTS AFFECT WOMEN 1178 00:54:13,606 --> 00:54:17,143 MORE THAN MEN. 1179 00:54:17,143 --> 00:54:18,978 AND NOW THE DIFFERENT TYPES OF 1180 00:54:18,978 --> 00:54:22,081 LIVER CANCER IN ADULTS AND 1181 00:54:22,081 --> 00:54:27,920 CARCINOMA WHICH ARISES FROM THE 1182 00:54:27,920 --> 00:54:32,958 HEPATOCYTES 75% OF CASES AND 1183 00:54:32,958 --> 00:54:37,663 CHOL ANGIOCARCINOMA AND THE TWO 1184 00:54:37,663 --> 00:54:45,337 RARE CANCERS ANGIOSARCOMA AND 1185 00:54:45,337 --> 00:54:48,374 FIBROLAMELLAR CARCINOMA AND THEN 1186 00:54:48,374 --> 00:54:55,181 WE HAVE HEPATOBLASTOMA AND HCC. 1187 00:54:55,181 --> 00:54:58,884 YOU HAVE THE RATES FOR 20,000 1188 00:54:58,884 --> 00:55:02,588 PERSON BY 2020 BY COUNTRY. 1189 00:55:02,588 --> 00:55:09,361 YOU SEE THE VARIATION. 1190 00:55:09,361 --> 00:55:11,330 THE LOWEST RATES ARE IN CENTRAL 1191 00:55:11,330 --> 00:55:21,607 AND SOUTH ASIA. 1192 00:55:29,048 --> 00:55:30,916 THIS SHOWS THE MORTALITY RATE 1193 00:55:30,916 --> 00:55:35,521 PER 100,000 PERSONS BY COUNTRY. 1194 00:55:35,521 --> 00:55:36,789 THE INCIDENTS RATES IN THE 1195 00:55:36,789 --> 00:55:40,559 FORMER SLIDE AND THE LOWEST 1196 00:55:40,559 --> 00:55:41,927 MORTALITY RATES BEING IN SOUTH 1197 00:55:41,927 --> 00:55:45,598 AND CENTRAL ASIA AND THE HIGHEST 1198 00:55:45,598 --> 00:55:47,032 RATES BEING IN EAST AND 1199 00:55:47,032 --> 00:55:52,471 SOUTHEAST ASIA. 1200 00:55:52,471 --> 00:55:58,677 WITH RATES APPROACHING 16 PER 1201 00:55:58,677 --> 00:55:59,745 100,000 PERSONS. 1202 00:55:59,745 --> 00:56:03,949 THE HIGHEST RATES ARE IN 1203 00:56:03,949 --> 00:56:09,388 MONGOLIA A MORTALITY RATE AND 1204 00:56:09,388 --> 00:56:11,523 LOWEST IN SRI LANKA WHERE RATES 1205 00:56:11,523 --> 00:56:19,131 ARE 1.2 AND 1.3 PER 100,000 1206 00:56:19,131 --> 00:56:19,865 PERSONS RESPECTIVELY. 1207 00:56:19,865 --> 00:56:21,500 THE RATES ARE HIGHER IN MALES 1208 00:56:21,500 --> 00:56:24,503 COMPARED TO MALES. 1209 00:56:24,503 --> 00:56:28,440 THERE'S A SLIDE OF THE 1210 00:56:28,440 --> 00:56:30,943 MALE/FEMALE PER 100,000 PERSONS. 1211 00:56:30,943 --> 00:56:39,485 THE HCC IS SHOWN IN BLUE AND THE 1212 00:56:39,485 --> 00:56:43,389 ANGIOC 1213 00:56:43,389 --> 00:56:46,392 ANGIOC 1214 00:56:46,392 --> 00:56:47,192 ANGIO CAR 1215 00:56:47,192 --> 00:56:50,362 ANGIOCARCINOMA AND THERE'S 1.6 1216 00:56:50,362 --> 00:56:55,668 TO 1 IN THE CARIBBEAN AND 1217 00:56:55,668 --> 00:56:57,937 CENTRAL AMERICA TO HIGH IN 1218 00:56:57,937 --> 00:57:00,639 WESTERN EUROPE FOR 1219 00:57:00,639 --> 00:57:03,776 HEPATOCELLULAR CARCINOMA AND 1220 00:57:03,776 --> 00:57:06,545 THERE'S NOT AS DRAMATIC AS THE 1221 00:57:06,545 --> 00:57:09,882 SCENE IN THE HEPATOCELLULAR 1222 00:57:09,882 --> 00:57:14,320 CARCINOMA WHERE THE HIGHEST 1223 00:57:14,320 --> 00:57:24,596 PROPORTION OF MALES TO FEMALES 1224 00:57:24,596 --> 00:57:27,700 AND IS FLIPPED IN SOUTH AMERICA 1225 00:57:27,700 --> 00:57:31,236 WHERE FEMALES OUT NUMBER MALES 1226 00:57:31,236 --> 00:57:33,472 AND THE REASON FOR THE HIGHER 1227 00:57:33,472 --> 00:57:38,243 RATE REMAINS UNEXPLAINED. 1228 00:57:38,243 --> 00:57:43,182 SO THE ETIOLOGY ALSO VARIES 1229 00:57:43,182 --> 00:57:45,217 GLOBALLY. 1230 00:57:45,217 --> 00:57:47,386 AND IN EAST AND SOUTHEAST ASIA 1231 00:57:47,386 --> 00:57:49,588 MOST ARE RELATED TO CHRONIC 1232 00:57:49,588 --> 00:57:51,490 HEPATITIS B SHOWN BY THE ORANGE 1233 00:57:51,490 --> 00:57:52,891 PORTION OF THE PIE CHARTS. 1234 00:57:52,891 --> 00:57:55,394 WHEREAS IN CENTRAL EUROPE AND 1235 00:57:55,394 --> 00:57:58,063 EASTERN EUROPE MOST ARE RELATED 1236 00:57:58,063 --> 00:58:00,299 TO ALCOHOL SHOWN BY THE BLUE 1237 00:58:00,299 --> 00:58:04,703 PARTS OF THE PIE CHARTS AND IN 1238 00:58:04,703 --> 00:58:07,539 AFRICAN AND WESTERN EUROPE AND 1239 00:58:07,539 --> 00:58:09,541 NORTH AMERICA MOST ARE RELATED 1240 00:58:09,541 --> 00:58:12,277 TO CHRONIC HEPATITIS C SHOWN BY 1241 00:58:12,277 --> 00:58:17,950 THE GREEN PORTIONS. 1242 00:58:17,950 --> 00:58:20,285 GLOBALLY IT ACCOUNTS FOR IT 42% 1243 00:58:20,285 --> 00:58:22,054 OF CASES. 1244 00:58:22,054 --> 00:58:25,524 FOLLOWED BY ALCOHOL AND THEN 1245 00:58:25,524 --> 00:58:26,725 HEPATITIS C. 1246 00:58:26,725 --> 00:58:35,200 ONE POINT I'D LIKE TO MENTION IS 1247 00:58:35,200 --> 00:58:38,303 NON-ALCOHOLIC LIVER DISEASE 1248 00:58:38,303 --> 00:58:40,506 METABOLIC LIVER DISEASE IS NOW 1249 00:58:40,506 --> 00:58:43,909 AN EMERGING CAUSE IN THE ABSENCE 1250 00:58:43,909 --> 00:58:45,677 OF CIRRHOSIS IN WESTERN 1251 00:58:45,677 --> 00:58:51,150 COUNTRIES. 1252 00:58:51,150 --> 00:58:53,552 FOR THE REST OF THE TALK I'M 1253 00:58:53,552 --> 00:58:56,522 GOING TO TALK ABOUT THE 1254 00:58:56,522 --> 00:58:59,258 HEPATOCELLULAR CARCINOMA AND 1255 00:58:59,258 --> 00:59:00,659 TALK ABOUT SCREENING AND HOW WE 1256 00:59:00,659 --> 00:59:03,762 IDENTIFY CANCERS IN PATIENTS WHO 1257 00:59:03,762 --> 00:59:04,630 ARE AT RISK. 1258 00:59:04,630 --> 00:59:07,900 AND WHY DO WE SCREEN FOR HCC? 1259 00:59:07,900 --> 00:59:09,768 THAT IS BECAUSE TUMOR STAGE OF 1260 00:59:09,768 --> 00:59:10,736 PRESENTATION HAS BEEN SHOWN TO 1261 00:59:10,736 --> 00:59:14,139 BE THE STRONGEST PREDICTOR OF 1262 00:59:14,139 --> 00:59:16,575 OUTCOME IN PERSONS WHO PRESENT 1263 00:59:16,575 --> 00:59:18,243 WITH EARLIER STAGE DISEASE 1264 00:59:18,243 --> 00:59:20,846 AMENABLE TO CURATIVE THERAPY THE 1265 00:59:20,846 --> 00:59:22,681 MEDIAN SURVIVAL IS GOOD FIVE TO 1266 00:59:22,681 --> 00:59:23,515 10 YEARS. 1267 00:59:23,515 --> 00:59:25,350 IN CONTRAST INDIVIDUALS 1268 00:59:25,350 --> 00:59:26,852 PRESENTING WITH LATE STAGE 1269 00:59:26,852 --> 00:59:29,555 DISEASE WHOSE TUMORS ARE ONLY 1270 00:59:29,555 --> 00:59:31,523 AMENABLE TO PALLIATIVE THERAPY 1271 00:59:31,523 --> 00:59:37,863 THE SURVIVAL IS POOR, 1-3 YEARS. 1272 00:59:37,863 --> 00:59:44,436 THERE'S DATA FROM RANDOMIZED 1273 00:59:44,436 --> 00:59:47,272 TRIALS AND OVER 18,000 POSITIVE 1274 00:59:47,272 --> 00:59:51,577 SUBJECTS WERE RANDOMIZED TO 1275 00:59:51,577 --> 00:59:54,046 RECEIVE ULTRASOUND PLUS 1276 00:59:54,046 --> 00:59:55,114 SURVEILLANCE AND COMPLIANCE WAS 1277 00:59:55,114 --> 00:59:59,318 ONLY 58% BUT DESPITE THAT AMONG 1278 00:59:59,318 --> 01:00:04,389 THE SCREENED GROUP A GREATER 1279 01:00:04,389 --> 01:00:07,326 PROPORTION WAS IDENTIFIED AT 60% 1280 01:00:07,326 --> 01:00:10,162 COMPARED TO 0% OF THE CONTROL 1281 01:00:10,162 --> 01:00:10,863 GROUP. 1282 01:00:10,863 --> 01:00:14,399 HAD TUMORS THAT WERE ABLE TO 1283 01:00:14,399 --> 01:00:17,669 UNDERGO CURATIVE RESECTION, 47% 1284 01:00:17,669 --> 01:00:20,272 VERSUS 8% AND HAD SIGNIFICANTLY 1285 01:00:20,272 --> 01:00:23,142 BETTER FIVE-YEAR SURVIVAL RATES 1286 01:00:23,142 --> 01:00:25,744 APPROACHING 50% IN THE SCREENED 1287 01:00:25,744 --> 01:00:27,513 GROUP COMPARED TO ZERO IN THE 1288 01:00:27,513 --> 01:00:28,914 NOT SCREENED GROUP. 1289 01:00:28,914 --> 01:00:31,283 TWICE YEARLY SCREENING WAS SHOWN 1290 01:00:31,283 --> 01:00:38,390 TO REDUCE MORTALITY BY 37%. 1291 01:00:38,390 --> 01:00:41,894 WOULD YOU GET SIMILAR RESULTS IN 1292 01:00:41,894 --> 01:00:52,337 A POPULATION COMPLETELY SIR 1293 01:00:52,337 --> 01:01:02,881 CIRRHOTIC AND MAYBE THERE'S ALSO 1294 01:01:08,620 --> 01:01:12,357 SHOWING HCC SURVEILLANCE 1295 01:01:12,357 --> 01:01:13,525 IMPROVES SURVIVAL. 1296 01:01:13,525 --> 01:01:14,960 THIS SLIDE SHOWS META-ANALYSIS 1297 01:01:14,960 --> 01:01:17,930 OF 12 STUDIES WHICH CONTROL TO 1298 01:01:17,930 --> 01:01:20,766 LEAD TIME BIAS SHOWING THAT 1299 01:01:20,766 --> 01:01:25,103 SURVEILLANCE WAS ASSOCIATED WITH 1300 01:01:25,103 --> 01:01:29,675 A 33% IMPROVEMENT IN SURVIVAL 1301 01:01:29,675 --> 01:01:32,644 COMPARED TO PATIENTS RECEIVING 1302 01:01:32,644 --> 01:01:34,713 SCREENING. 1303 01:01:34,713 --> 01:01:36,915 WHO IS AT RISK? 1304 01:01:36,915 --> 01:01:40,485 THESE ARE SHOWN ON THE SLIDE 1305 01:01:40,485 --> 01:01:40,752 HERE. 1306 01:01:40,752 --> 01:01:42,521 PERSONS WITH CIRRHOSIS THAT IS 1307 01:01:42,521 --> 01:01:45,591 WELL COMPENSATED AOB OF ANY 1308 01:01:45,591 --> 01:01:49,661 ETIOLOGY OR CANDIDATES TO UNDER 1309 01:01:49,661 --> 01:01:57,536 GO SURVEILLANCE AND TRANSPLANT 1310 01:01:57,536 --> 01:01:59,838 CANDIDATES SHOULD UNDER GO AND 1311 01:01:59,838 --> 01:02:00,639 THOSE WITH INCREASED RISK OF 1312 01:02:00,639 --> 01:02:08,847 CANCER AS SHOWN HERE. 1313 01:02:08,847 --> 01:02:18,323 AND THOSE WITH NON-CIRRHOTIC OR 1314 01:02:18,323 --> 01:02:19,057 NON-ALCOHOL LIVER DISEASE 1315 01:02:19,057 --> 01:02:21,393 BENEFIT FROM SURVEILLANCE. 1316 01:02:21,393 --> 01:02:25,297 WHAT TEST DO WE SCREEN WITH? 1317 01:02:25,297 --> 01:02:26,999 ULTRASOUND IS THE MODALITY OF 1318 01:02:26,999 --> 01:02:29,001 CHOICE BECAUSE IT'S WIDELY 1319 01:02:29,001 --> 01:02:32,070 AVAILABLE, SAFE AND RELATIVELY 1320 01:02:32,070 --> 01:02:33,538 INEXPENSIVE. 1321 01:02:33,538 --> 01:02:44,049 IT IT'S BEEN SHOWN TO BE COST 1322 01:02:55,093 --> 01:02:56,261 EFFECTIVE THEREFORE THE AMERICAN 1323 01:02:56,261 --> 01:02:58,330 ASSOCIATION FOR THE STUDY OF 1324 01:02:58,330 --> 01:03:01,566 AMERICAN LIVER DISEASES DOES 1325 01:03:01,566 --> 01:03:06,271 RECOMMEND ULTRASOUND AS THE 1326 01:03:06,271 --> 01:03:09,541 SCREENING MODALITY AND THE 1327 01:03:09,541 --> 01:03:10,442 OPTIMAL IS FOUR TO EIGHT MONTHS 1328 01:03:10,442 --> 01:03:13,512 BASED ON TUMOR TIME OF 1329 01:03:13,512 --> 01:03:17,015 APPROXIMATELY SIX MONTHS. 1330 01:03:17,015 --> 01:03:18,984 THERE ARE LIMITATIONS OF THE 1331 01:03:18,984 --> 01:03:22,821 SCREENING METHODS AND ULTRASOUND 1332 01:03:22,821 --> 01:03:25,057 IS DEPENDENT ON THE OPERATORS 1333 01:03:25,057 --> 01:03:26,858 AND SEVERITY OF LIVER DISEASE 1334 01:03:26,858 --> 01:03:27,926 AND ADHERENCE. 1335 01:03:27,926 --> 01:03:31,063 THE OPTIMAL SCREENING INTERVAL 1336 01:03:31,063 --> 01:03:34,399 IS CURRENTLY BASED ON A 1337 01:03:34,399 --> 01:03:34,866 SIX-MONTH INTERVAL. 1338 01:03:34,866 --> 01:03:36,601 IT'S BASED ON TUMOR DOUBLING 1339 01:03:36,601 --> 01:03:41,773 TIME AND WE KNOW HCC TUMORS ARE 1340 01:03:41,773 --> 01:03:43,108 QUITE HETEROGENEOUS. 1341 01:03:43,108 --> 01:03:45,510 SCREENING RATES ARE LOW. 1342 01:03:45,510 --> 01:03:46,845 FEWER THAN 50% OF NEWLY 1343 01:03:46,845 --> 01:03:49,581 DIAGNOSED HCCs ARE DETECTED BY 1344 01:03:49,581 --> 01:03:50,082 SCREENING. 1345 01:03:50,082 --> 01:03:53,185 IT'S UNCLEAR IF IT'S BENEFICIAL 1346 01:03:53,185 --> 01:03:54,553 FOR POPULATIONS IN WHOM THERE'S 1347 01:03:54,553 --> 01:03:58,890 A LACK OF ACCESS TO CURE 1348 01:03:58,890 --> 01:03:59,591 OPTIONS. 1349 01:03:59,591 --> 01:04:00,759 GIVEN THE LIMITATIONS THERE'S 1350 01:04:00,759 --> 01:04:01,927 CLEARLY A NEED FOR BETTER 1351 01:04:01,927 --> 01:04:05,530 SCREENING STRATEGIES. 1352 01:04:05,530 --> 01:04:16,608 SOME EMERGING STRATEG STRATEGIE 1353 01:04:24,883 --> 01:04:27,386 ULTRASOUND FOR EARLY AND 86% IN 1354 01:04:27,386 --> 01:04:30,489 THE VERSUS 26% IN THE CASE OF 1355 01:04:30,489 --> 01:04:33,225 MR. 1356 01:04:33,225 --> 01:04:34,860 THEY'RE ASSOCIATED WITH DOWN 1357 01:04:34,860 --> 01:04:39,765 SIDES. 1358 01:04:39,765 --> 01:04:43,602 AND REPEATED CT IMAGING AND 1359 01:04:43,602 --> 01:04:51,576 ISSUES WITH CAPACITY AND COST 1360 01:04:51,576 --> 01:04:51,943 WITH MRI. 1361 01:04:51,943 --> 01:04:58,884 THERE'S BLOOD BASED MARKERS. 1362 01:04:58,884 --> 01:05:00,485 UNFORTUNATELY THEY HAVE LOW 1363 01:05:00,485 --> 01:05:03,789 SENSITIVITY AND SPECIFICITY FOR 1364 01:05:03,789 --> 01:05:06,258 DETECTION OF EARLY TUMORS IN 1365 01:05:06,258 --> 01:05:07,259 CASE CONTROL STUDIES. 1366 01:05:07,259 --> 01:05:11,363 BUT THERE IS ONE I DID WANT TO 1367 01:05:11,363 --> 01:05:15,967 HIGHLIGHT AND THIS IS GALADD 1368 01:05:15,967 --> 01:05:21,540 WHICH ENCOMPASSES GENDER, AGE, 1369 01:05:21,540 --> 01:05:21,840 PROTEIN L3 AND 1370 01:05:24,609 --> 01:05:27,279 DCP SHOWN TO HAVE HIGH 1371 01:05:27,279 --> 01:05:29,281 SENSITIVITY IN PATIENTS WITH 1372 01:05:29,281 --> 01:05:30,949 CIRRHOSIS. 1373 01:05:30,949 --> 01:05:34,119 THOUGH IN THIS ANALYSIS HERE IT 1374 01:05:34,119 --> 01:05:39,057 SEEMED TO PERFORM AS THE PROTEIN 1375 01:05:39,057 --> 01:05:41,460 L3 BY ITSELF. 1376 01:05:41,460 --> 01:05:44,362 NEVERTHELESS IT'S UNDERGOING 1377 01:05:44,362 --> 01:05:45,530 CONTINUED ASSESSMENT AND 1378 01:05:45,530 --> 01:05:50,035 CURRENTLY IN A RANDOMIZED 1379 01:05:50,035 --> 01:05:53,538 CONTROL PHASE 4 STUDY TO COMPARE 1380 01:05:53,538 --> 01:05:56,775 TO ULTRASOUND FOR EARLY 1381 01:05:56,775 --> 01:06:00,512 DETECTION OF HEPATOCELLULAR 1382 01:06:00,512 --> 01:06:02,380 CARCINOMA BEING THE END POINT. 1383 01:06:02,380 --> 01:06:05,217 THERE'S GREAT INTEREST IN 1384 01:06:05,217 --> 01:06:07,552 LOOKING AT LIQUID BIOPSY AS A 1385 01:06:07,552 --> 01:06:09,955 BIOMARKERS FOR EARLY DETECTION 1386 01:06:09,955 --> 01:06:12,624 OF HCC AND INCLUDE LOOKING AT 1387 01:06:12,624 --> 01:06:15,961 DNA FRAGMENTS, LOOKING AT EXTRA 1388 01:06:15,961 --> 01:06:21,533 CELLULAR VESICLES OR EVEN TUMOR 1389 01:06:21,533 --> 01:06:25,003 CELLS THEMSELVES. 1390 01:06:25,003 --> 01:06:28,206 NOW, BECAUSE METHYLATION IS AN 1391 01:06:28,206 --> 01:06:36,414 EARLY STEP IN HEPATO PAPATHOGENS 1392 01:06:36,414 --> 01:06:39,451 THERE'S METHYLATION BEING PUR 1393 01:06:39,451 --> 01:06:41,520 AND COMPANIES HAVE DEVELOPED 1394 01:06:41,520 --> 01:06:43,188 TEST FOR HYPERMETHYLATION 1395 01:06:43,188 --> 01:06:46,992 CURRENTLY AVAILABLE AND CAN BE 1396 01:06:46,992 --> 01:06:47,826 PURCHASED. 1397 01:06:47,826 --> 01:06:52,464 HOWEVER, THERE'S A NUMBER OF 1398 01:06:52,464 --> 01:06:53,832 ISSUES THAT NEED TO BE RESOLVED 1399 01:06:53,832 --> 01:06:56,535 AND CHALLENGES AND LOW SENSITIVE 1400 01:06:56,535 --> 01:06:58,169 AND ISSUES WITH STANDARDIZATION 1401 01:06:58,169 --> 01:06:58,937 AND THE DIFFICULTY OF 1402 01:06:58,937 --> 01:07:03,575 REPLICATING A FAVORABLE 1403 01:07:03,575 --> 01:07:05,210 MICROENVIRONMENT THAT CAN 1404 01:07:05,210 --> 01:07:07,812 MAINTAIN CIRCULATING TUMOR CELLS 1405 01:07:07,812 --> 01:07:08,713 TO ALLOW THESE TYPES OF STUDIES 1406 01:07:08,713 --> 01:07:18,223 TO BE PERFORMED. 1407 01:07:18,223 --> 01:07:21,426 THERE'S UNANSWERED QUESTIONS AND 1408 01:07:21,426 --> 01:07:24,329 THE IMAGING PLUS THE BIOMARKER 1409 01:07:24,329 --> 01:07:26,364 AND WHAT SHOULD THE FREQUENCY 1410 01:07:26,364 --> 01:07:26,565 BE? 1411 01:07:26,565 --> 01:07:28,433 EVERY SIX MONTHS OR THREE 1412 01:07:28,433 --> 01:07:29,100 MONTHS? 1413 01:07:29,100 --> 01:07:31,736 A RECENT STUDY SHOWED A SHORTER 1414 01:07:31,736 --> 01:07:33,738 INTERVAL OF THREE MONTHS WAS FLO 1415 01:07:33,738 --> 01:07:36,408 BETTER COMPARED TO SIX MONTHS. 1416 01:07:36,408 --> 01:07:37,542 SECOND, THEY SHOULD BE MOVED TO 1417 01:07:37,542 --> 01:07:44,583 PRECISION SCREENING. 1418 01:07:44,583 --> 01:07:51,156 FOR EXAMPLE, ULTRASOUND PLUS THE 1419 01:07:51,156 --> 01:07:54,593 PROTEIN IS NOT SUFFICIENT IN 1420 01:07:54,593 --> 01:07:56,094 NON-OBESE PATIENTS COMPARED TO 1421 01:07:56,094 --> 01:08:00,966 MORE SENSITIVE IMAGING AND 1422 01:08:00,966 --> 01:08:02,500 BLOOD-BASED STRATEGIES MAY BE 1423 01:08:02,500 --> 01:08:05,136 MORE EFFECTIVE IN OBESE AND 1424 01:08:05,136 --> 01:08:06,905 SHOULD IT DIFFER FROM HCC RISK 1425 01:08:06,905 --> 01:08:09,574 AND THE HIGHEST PATIENTS BENEFIT 1426 01:08:09,574 --> 01:08:16,047 FROM MORE INTENSIVE SCREENING MR 1427 01:08:16,047 --> 01:08:22,520 OR CT AND OTHERS ULTRA SOUND 1428 01:08:22,520 --> 01:08:24,322 WITH OR WITHOUT A BIOMARKER. 1429 01:08:24,322 --> 01:08:26,858 ONCE A LESION HAS BEEN 1430 01:08:26,858 --> 01:08:28,026 IDENTIFIED IN AN AT RISK 1431 01:08:28,026 --> 01:08:31,096 INDIVIDUAL THE NEXT STEP IS TO 1432 01:08:31,096 --> 01:08:34,733 DIAGNOSE WHETHER IT'S INDEED HCC 1433 01:08:34,733 --> 01:08:40,505 OR NOT. 1434 01:08:40,505 --> 01:08:42,774 AND THERE'S MODALITY FOR 1435 01:08:42,774 --> 01:08:44,442 DIAGNOSIS. 1436 01:08:44,442 --> 01:08:48,647 THE BIOPSY IS NOT ROUTINELY 1437 01:08:48,647 --> 01:08:53,518 REQUIRED BECAUSE OF THE 1438 01:08:53,518 --> 01:08:55,420 SPECIFICITY AND THE CHOICE OF 1439 01:08:55,420 --> 01:09:00,692 USING CT OR MR DEPENDS ON 1440 01:09:00,692 --> 01:09:04,029 FACTORS I WON'T GO INTO IN ANY 1441 01:09:04,029 --> 01:09:08,967 DETAIL. 1442 01:09:08,967 --> 01:09:13,438 GIVEN THE DEPENDENCE OF ACC, 1443 01:09:13,438 --> 01:09:15,273 RADIO LOGIC CLASSIFICATION WAS 1444 01:09:15,273 --> 01:09:20,445 DEVELOPED TO TRY TO STANDARDIZE 1445 01:09:20,445 --> 01:09:24,616 THE REPORTING AND INTERPRETATION 1446 01:09:24,616 --> 01:09:28,720 OF IMAGING TESTS. 1447 01:09:28,720 --> 01:09:31,723 AND TO COME UP WITH THE 1448 01:09:31,723 --> 01:09:32,590 LIKELIHOOD SCORE THE LESION 1449 01:09:32,590 --> 01:09:37,529 OBSERVED IS LIKELY TO BE A 1450 01:09:37,529 --> 01:09:40,065 HEPATOCELLULAR CARCINOMA AND 1451 01:09:40,065 --> 01:09:49,541 THERE'S SEVEN CATEGORIES AND 1452 01:09:49,541 --> 01:09:54,012 ASSIGNS THE SCORE USING ARTERIAL 1453 01:09:54,012 --> 01:09:55,880 PHASE, HYPERENHANCEMENT AND SIZE 1454 01:09:55,880 --> 01:09:59,484 OF THE LESION AND ENHANCING 1455 01:09:59,484 --> 01:10:01,586 CAPSULE, NON PERATIVE VAL WASH 1456 01:10:01,586 --> 01:10:04,355 OUT OR INTERVAL THRESHOLD 1457 01:10:04,355 --> 01:10:05,290 GROWTH. 1458 01:10:05,290 --> 01:10:08,927 AGE THE CATEGORIES ONE AND TWO 1459 01:10:08,927 --> 01:10:13,098 ARE BENIGN LESIONS AND GENERALLY 1460 01:10:13,098 --> 01:10:21,806 DON'T REQUIRE FOLLOW-UP AND THE 1461 01:10:21,806 --> 01:10:23,441 INTERMEDIATE PROBABILITY AND 5 1462 01:10:23,441 --> 01:10:27,212 IS DEFINITE HCC. 1463 01:10:27,212 --> 01:10:28,279 THERE'S TWO ADDITIONAL 1464 01:10:28,279 --> 01:10:34,886 CATEGORIES WHICH STAND FOR 1465 01:10:34,886 --> 01:10:36,254 METASTATIC MALIGNANT DISEASE 1466 01:10:36,254 --> 01:10:40,024 WHICH IS NOT PRIMARY HCC BUT 1467 01:10:40,024 --> 01:10:41,860 LIKELY METASTATIC DISEASE AND 1468 01:10:41,860 --> 01:10:46,030 TIV FOR TUMOR IN VAIN. 1469 01:10:46,030 --> 01:10:47,665 -- TUMOR IN VEIN. 1470 01:10:47,665 --> 01:10:49,701 BECAUSE OF THE CLOSE ASSOCIATION 1471 01:10:49,701 --> 01:10:53,538 BETWEEN THE CATEGORY AND RISK OF 1472 01:10:53,538 --> 01:10:57,542 LESION BEING HCC, WE CAN ALSO 1473 01:10:57,542 --> 01:10:59,811 USE IT TO DETERMINE THE 1474 01:10:59,811 --> 01:11:01,513 SUBSEQUENT FOLLOW-UP OF LESIONS 1475 01:11:01,513 --> 01:11:04,082 DETECTED AND THAT'S SHOWN HERE 1476 01:11:04,082 --> 01:11:06,151 ON THIS SLIDE. 1477 01:11:06,151 --> 01:11:12,290 SO LIRADS 1 AND 2 PROBABLY 1478 01:11:12,290 --> 01:11:16,027 BENIGN CAN RETURN TO 1479 01:11:16,027 --> 01:11:18,696 SURVEILLANCE. 1480 01:11:18,696 --> 01:11:24,269 LIRADS ARE 20% TO 40% BEING ATC 1481 01:11:24,269 --> 01:11:28,106 SHOULD UNDER GO REPEAT IMAGING 1482 01:11:28,106 --> 01:11:33,812 WITH A MODALITY MORE SENSITIVE 1483 01:11:33,812 --> 01:11:36,815 AND IN THE SURVEILLANCE INTERVAL 1484 01:11:36,815 --> 01:11:38,216 REDUCED TO LIKELY THREE MONTHS. 1485 01:11:38,216 --> 01:11:43,755 FOR LESIONS, LIRADS 4 AND 5 1486 01:11:43,755 --> 01:11:46,324 REPRESENT PROBABLE HCC OR 1487 01:11:46,324 --> 01:11:48,092 DEFINITE HCC SUBSEQUENT 1488 01:11:48,092 --> 01:11:51,196 FOLLOW-UP SHOULD BE BASED ON 1489 01:11:51,196 --> 01:11:55,033 PRESENTATION OF THE CASE TO 1490 01:11:55,033 --> 01:11:57,635 MULTIDISCIPLINARY ROUNDS FOR 1491 01:11:57,635 --> 01:11:58,136 CONSENSUS FOR FURTHER 1492 01:11:58,136 --> 01:12:03,007 EVALUATION. 1493 01:12:03,007 --> 01:12:06,311 FINALLY, FOR THE LAST TWO STAGES 1494 01:12:06,311 --> 01:12:11,282 M AND TIV AND THERE WERE 1495 01:12:11,282 --> 01:12:11,916 DISCUSSIONS FOR TAILORED WORK 1496 01:12:11,916 --> 01:12:18,556 UP. 1497 01:12:18,556 --> 01:12:19,290 THE NEXT STEP FOLLOWING 1498 01:12:19,290 --> 01:12:20,658 DIAGNOSIS IS TO STAGE THE EXTENT 1499 01:12:20,658 --> 01:12:24,729 OF THE DISEASE. 1500 01:12:24,729 --> 01:12:29,133 NOW, UNLIKE OTHER CANCERS, TUMOR 1501 01:12:29,133 --> 01:12:32,503 BURDEN ALONE IS NOT THE ONLY 1502 01:12:32,503 --> 01:12:33,004 PREDICTOR MUCH OUTCOME. 1503 01:12:33,004 --> 01:12:33,538 -- OF OUTCOME. 1504 01:12:33,538 --> 01:12:38,877 AND OTHER FACTORS SUCH AS THE 1505 01:12:38,877 --> 01:12:41,913 SEVERITY OF THE UNDERLYING LIVER 1506 01:12:41,913 --> 01:12:45,717 DISEASE AND PERFORMANCE OF THE 1507 01:12:45,717 --> 01:12:47,652 INDIVIDUAL ARE IMPORTANT THAT 1508 01:12:47,652 --> 01:12:52,123 DETERMINE OUTCOME OF HCC. 1509 01:12:52,123 --> 01:12:55,526 THEREFORE A NUMBER OF STAGES 1510 01:12:55,526 --> 01:12:58,529 SYSTEMS HAVE BEEN DEVELOPED. 1511 01:12:58,529 --> 01:13:01,599 THE MOST COMMONLY USED IS THE 1512 01:13:01,599 --> 01:13:04,969 BARCELONA CLINIC LIVER CANCER 1513 01:13:04,969 --> 01:13:05,536 STAGING SYSTEM. 1514 01:13:05,536 --> 01:13:13,044 THIS HAS FIVE STAGES AND A 1515 01:13:13,044 --> 01:13:16,414 THROUGH D AND B INTERMEDIATE AND 1516 01:13:16,414 --> 01:13:26,424 C ADVANCED AND D TERMINAL STAGE. 1517 01:13:26,424 --> 01:13:27,392 THE ADVANTAGE OF THE SYSTEM IS 1518 01:13:27,392 --> 01:13:30,328 IT'S BEEN VALIDATED IN MULTIPLE 1519 01:13:30,328 --> 01:13:33,197 POPULATIONS AND IT ALLOWS US TO 1520 01:13:33,197 --> 01:13:35,400 RISK STRATIFY PATIENTS IN TERMS 1521 01:13:35,400 --> 01:13:40,071 OF THEIR PROGNOSIS. 1522 01:13:40,071 --> 01:13:42,674 IN 2022 THE BCLC STAGING SYSTEM 1523 01:13:42,674 --> 01:13:45,510 WAS UPDATED TO INCLUDE MORE 1524 01:13:45,510 --> 01:13:48,880 OBJECTIVE CRITERIA ON THE 1525 01:13:48,880 --> 01:13:49,747 UNDERLYING LIVER DISEASE 1526 01:13:49,747 --> 01:13:52,650 INCLUDING INCORPORATION OF 1527 01:13:52,650 --> 01:13:55,320 MODELS OF UNDERLYING LIVER 1528 01:13:55,320 --> 01:13:58,089 DISEASE SUCH AS THE MODEL FOR 1529 01:13:58,089 --> 01:14:01,526 END STAGE LIVER DISEASE USED TO 1530 01:14:01,526 --> 01:14:04,829 ASSIGN ORGANS TO PATIENTS FOR 1531 01:14:04,829 --> 01:14:14,539 LIVER TRANSPLANTATION AND THIS 1532 01:14:14,539 --> 01:14:16,174 ALLOWS MORE OBJECTIVE ASSESSMENT 1533 01:14:16,174 --> 01:14:19,243 OF UNDERLYING LIVER DISEASE. 1534 01:14:19,243 --> 01:14:23,014 FOR YOUR KNOWLEDGE I'VE INCLUDED 1535 01:14:23,014 --> 01:14:27,051 THE ONCOLOGY GROUP DESCRIPTORS 1536 01:14:27,051 --> 01:14:29,387 FOR FUNCTIONAL STATUS USED AS 1537 01:14:29,387 --> 01:14:31,789 PART OF THE BARCELONA CLINIC 1538 01:14:31,789 --> 01:14:33,024 CANCER SCORING SYSTEM. 1539 01:14:33,024 --> 01:14:35,960 OTHER IMPORTANT CAVEATS OF THE 1540 01:14:35,960 --> 01:14:41,532 BCLC STAGING SYSTEM IS IT ALLOWS 1541 01:14:41,532 --> 01:14:52,043 FOR THE HETEROGENEITY OF THE 1542 01:15:02,620 --> 01:15:02,820 PATIENTS. 1543 01:15:02,820 --> 01:15:07,825 FOR THE BALANCE OF THE TALK I'M 1544 01:15:07,825 --> 01:15:10,962 TALK ABOUT TREATMENT. 1545 01:15:10,962 --> 01:15:13,131 THERE'S BEEN SIGNIFICANT 1546 01:15:13,131 --> 01:15:15,199 DEVELOPMENT IN THE TREATMENTS 1547 01:15:15,199 --> 01:15:16,601 FOR HEPATITIS B PARTICULARLY 1548 01:15:16,601 --> 01:15:18,803 SYSTEMIC THERAPY. 1549 01:15:18,803 --> 01:15:20,371 I'LL TOUCH UPON THOSE LATER IN 1550 01:15:20,371 --> 01:15:21,239 THE TALK. 1551 01:15:21,239 --> 01:15:22,540 BROADLY WE CAN VIEW TREATMENTS 1552 01:15:22,540 --> 01:15:27,779 FOR HCC AS THOSE CURATIVE AND 1553 01:15:27,779 --> 01:15:32,850 THOSE NON-CURATIVE. 1554 01:15:32,850 --> 01:15:34,919 CURATIVE TRIES TO REMOVE 1555 01:15:34,919 --> 01:15:36,254 COMPLETELY THROUGH RESURGICAL 1556 01:15:36,254 --> 01:15:37,522 RESECTION OR LIVER 1557 01:15:37,522 --> 01:15:46,164 TRANSPLANTATION OR ABLATION. 1558 01:15:46,164 --> 01:15:49,333 WHEN YOU APPROACH IS PALLIATIVE 1559 01:15:49,333 --> 01:15:53,538 AND SOME QUALITY OF LIFE THROUGH 1560 01:15:53,538 --> 01:16:00,378 OTHER MEASURES SUCH AS TUMOR 1561 01:16:00,378 --> 01:16:08,386 EMBOWLIZATION AND STEREO TACTIC 1562 01:16:08,386 --> 01:16:11,789 BODY RADIATION AND BECAUSE OF 1563 01:16:11,789 --> 01:16:22,266 THE TYPES OF THERAPIES, AND 1564 01:16:27,305 --> 01:16:29,707 THERE'S ONCOLOGIST AND 1565 01:16:29,707 --> 01:16:36,647 PATHOLOGIST INVOLVED. 1566 01:16:36,647 --> 01:16:38,116 A LOT OF THE EVIDENCE USED TO 1567 01:16:38,116 --> 01:16:39,217 ASSESS TREATMENT HAS COME FROM 1568 01:16:39,217 --> 01:16:42,120 SMALL COHORT STUDIES BUT THERE'S 1569 01:16:42,120 --> 01:16:44,422 SOME CONTROLLED RANDOMIZED 1570 01:16:44,422 --> 01:16:47,558 STUDIES PROVIDED DATA AND THE 1571 01:16:47,558 --> 01:16:51,863 RECENT META-ANALYSIS HAS SHOWN 1572 01:16:51,863 --> 01:16:53,531 SURGICAL RESECTION LIVER 1573 01:16:53,531 --> 01:17:00,104 TRANSPLANTATION ABLATION CHEMO 1574 01:17:00,104 --> 01:17:01,806 ABLATION AND IMMUNE CHECKPOINT 1575 01:17:01,806 --> 01:17:04,275 INHIBITORS HAVE BEEN ASSOCIATED 1576 01:17:04,275 --> 01:17:11,315 WITH INCREASED SURVIVAL. 1577 01:17:11,315 --> 01:17:13,951 THIS ALGORITHM SHOWS THE 1578 01:17:13,951 --> 01:17:17,989 RECOMMENDATIONS OF THE BARCELONA 1579 01:17:17,989 --> 01:17:21,526 CLINIC CANCER STAGE BASED ON 1580 01:17:21,526 --> 01:17:22,393 LIVER BURDEN AND FUNCTION 1581 01:17:22,393 --> 01:17:24,195 SEVERITY AND PHYSICAL STATUS. 1582 01:17:24,195 --> 01:17:27,765 FOR PATIENTS WITH EARLY STAGE 1583 01:17:27,765 --> 01:17:36,874 DISEASE THEY'RE EXPECTED 1584 01:17:36,874 --> 01:17:37,508 SURVIVAL IS GREATER THAN FIVE 1585 01:17:37,508 --> 01:17:40,478 YEARS. 1586 01:17:40,478 --> 01:17:42,280 FOR THOSE WITH INTERMEDIATE 1587 01:17:42,280 --> 01:17:45,316 STAGE DISEASE, THESE PATIENTS 1588 01:17:45,316 --> 01:17:48,186 ARE BEST MANAGED WITH CASE OR 1589 01:17:48,186 --> 01:17:50,555 TRANS TUMOR ARTERIALIZATION AND 1590 01:17:50,555 --> 01:18:01,098 THEIR SUR VIVAL IS 3 TO 5 YEARS 1591 01:18:04,202 --> 01:18:06,837 AND TERMINAL STAGE DISEASE OR 1592 01:18:06,837 --> 01:18:09,774 STAGE D BEST MARKED WITH BETH 1593 01:18:09,774 --> 01:18:11,275 SUPPORTING YEAR AND THEIR OVER 1594 01:18:11,275 --> 01:18:12,109 ALL SURVIVAL IS ONLY ABOUT THREE 1595 01:18:12,109 --> 01:18:15,813 MONTHS. 1596 01:18:15,813 --> 01:18:21,519 NOW, THIS ALGORITHM I SHOWED YOU 1597 01:18:21,519 --> 01:18:23,688 HE 1598 01:18:23,688 --> 01:18:25,223 HERE IN GENERALIZATION AND THE 1599 01:18:25,223 --> 01:18:26,123 APPROACH FROM AN INDIVIDUAL 1600 01:18:26,123 --> 01:18:27,225 PATIENT IS MORE NUANCES. 1601 01:18:27,225 --> 01:18:29,794 WHAT I WANTED TO INTRODUCE HERE 1602 01:18:29,794 --> 01:18:33,531 WAS AN EMERGING CONCEPT AND THAT 1603 01:18:33,531 --> 01:18:36,334 IS OF TREATMENT STAGE MIGRATION. 1604 01:18:36,334 --> 01:18:38,169 WHERE IF A PATIENT MIGRATES OUT 1605 01:18:38,169 --> 01:18:41,672 OF A STAGE AND NO LONGER ABLE TO 1606 01:18:41,672 --> 01:18:43,674 RECEIVE THE RECOMMENDED APPROVED 1607 01:18:43,674 --> 01:18:46,611 THERAPY FOR THAT PARTICULAR 1608 01:18:46,611 --> 01:18:51,249 STAGE, ONE CAN EITHER USE AN 1609 01:18:51,249 --> 01:18:53,951 ALTERNATIVE THERAPY AVAILABLE 1610 01:18:53,951 --> 01:18:57,555 FOR THE SAME STAGE OR TRANSITION 1611 01:18:57,555 --> 01:18:59,190 TO THE NEXT ADVANCED STAGE AND 1612 01:18:59,190 --> 01:19:00,791 OFFER THE PATIENT THERAPY FOR 1613 01:19:00,791 --> 01:19:01,926 THAT STAGE. 1614 01:19:01,926 --> 01:19:03,861 FOR EXAMPLE, A PATIENT WITH 1615 01:19:03,861 --> 01:19:05,997 EARLY STAGE DISEASE WHO OTHER 1616 01:19:05,997 --> 01:19:12,236 WISE WOULD RECEIVE CURATIVE 1617 01:19:12,236 --> 01:19:17,041 TREATMENT MAY BENEFIT FROM CHEMO 1618 01:19:17,041 --> 01:19:18,409 LIBATION OR SYSTEMIC THERAPY AND 1619 01:19:18,409 --> 01:19:24,015 SO FORTH. 1620 01:19:24,015 --> 01:19:29,053 NOW LET'S LOOK AT THE MANAGEMENT 1621 01:19:29,053 --> 01:19:39,530 OF THROWS PATIENTS WITHOUT 1622 01:19:40,531 --> 01:19:43,734 CIRRHOSIS. 1623 01:19:43,734 --> 01:19:44,302 FOR PATIENTS WITH CIRRHOSIS 1624 01:19:44,302 --> 01:19:45,536 ADDITIONAL FACTORS NEED TO BE 1625 01:19:45,536 --> 01:19:45,836 CONSIDERED. 1626 01:19:45,836 --> 01:19:48,372 PARTICULARLY THE SEVERITY OF THE 1627 01:19:48,372 --> 01:19:50,308 UNDERLYING LIVER DISEASE AS WELL 1628 01:19:50,308 --> 01:19:52,009 AS THE FUNCTIONAL LIVER RESERVE. 1629 01:19:52,009 --> 01:19:53,978 HOW MUCH IS LEFT TO SUPPORT THE 1630 01:19:53,978 --> 01:19:54,211 PATIENT. 1631 01:19:54,211 --> 01:19:56,380 NOW, FOR INDIVIDUALS WITH A 1632 01:19:56,380 --> 01:19:59,583 SINGLE LIVER LESION WHO ARE WELL 1633 01:19:59,583 --> 01:20:02,753 COMPENSATED CIRRHOSIS IN THE 1634 01:20:02,753 --> 01:20:04,488 ABSENCE OF CLINICALLY 1635 01:20:04,488 --> 01:20:06,357 HYPERTENSION AND ESTIMATED LIVER 1636 01:20:06,357 --> 01:20:09,126 RESERVE OF MORE THAN 40%, SUCH 1637 01:20:09,126 --> 01:20:12,229 PATIENTS CAN BE MANAGED WITH 1638 01:20:12,229 --> 01:20:13,230 SURGICAL RESECTION AND THOSE 1639 01:20:13,230 --> 01:20:16,567 WITHIN THE CRITERIA CAN THEN BE 1640 01:20:16,567 --> 01:20:18,502 SALVAGED WITH LIVER 1641 01:20:18,502 --> 01:20:18,869 TRANSPLANTATION. 1642 01:20:18,869 --> 01:20:22,306 FOR THOSE INDIVIDUALS WHO HAVE 1643 01:20:22,306 --> 01:20:25,976 MORE THAN ONE LESION, THEY'RE 1644 01:20:25,976 --> 01:20:27,745 ELIGIBLE FOR LIVER 1645 01:20:27,745 --> 01:20:30,548 TRANSPLANTATION AND PATIENTS 1646 01:20:30,548 --> 01:20:34,251 WITH MORE THAN ONE LESION WITHIN 1647 01:20:34,251 --> 01:20:37,521 THE DOWN STAGING CRITERIA, THESE 1648 01:20:37,521 --> 01:20:39,457 SELECTED PATIENTS CAN BE DOWN 1649 01:20:39,457 --> 01:20:42,960 STAGED AND THEN OFFERED LIVER 1650 01:20:42,960 --> 01:20:43,661 TRANSPLANTATION AND HAVE GOOD 1651 01:20:43,661 --> 01:20:50,267 OUTCOMES. 1652 01:20:50,267 --> 01:20:55,406 SO I WANT TO REVIEW THE 1653 01:20:55,406 --> 01:20:57,508 CONTROVERSIES REGARDING 1654 01:20:57,508 --> 01:21:01,512 MANAGEMENT OF HEPATOCELLULAR 1655 01:21:01,512 --> 01:21:05,082 CARCINOMA PEOPLE I'LL BEGIN WITH 1656 01:21:05,082 --> 01:21:09,387 SURGICAL RESECTION OR ABLATION. 1657 01:21:09,387 --> 01:21:10,654 THEY GENERALLY HAVE A GOOD 1658 01:21:10,654 --> 01:21:12,890 PROGNOSIS BUT UP TO 1659 01:21:12,890 --> 01:21:15,659 THREE-QUARTERS MAY HAVE A TUMOR 1660 01:21:15,659 --> 01:21:17,061 RECURRENCE AT FIVE YEARS AND 1661 01:21:17,061 --> 01:21:20,631 THEIR ROLE FOR ADJUVANT THERAPY 1662 01:21:20,631 --> 01:21:25,269 TO REDUCE THIS RATE OF NON 1663 01:21:25,269 --> 01:21:26,904 RECURRENCE AND THE ANSWER HAS 1664 01:21:26,904 --> 01:21:27,872 BEEN EVOLVING. 1665 01:21:27,872 --> 01:21:29,540 WHEN I FIRST GAVE THIS TALK 1666 01:21:29,540 --> 01:21:32,343 ABOUT SEVEN OR EIGHT YEARS AGO 1667 01:21:32,343 --> 01:21:34,311 THE ANSWER WAS NO. 1668 01:21:34,311 --> 01:21:37,448 HOWEVER, IN 2023 THE ANSWER WAS 1669 01:21:37,448 --> 01:21:39,450 YES AND THAT'S BECAUSE DATA 1670 01:21:39,450 --> 01:21:41,118 BECAME AVAILABLE FROM 1671 01:21:41,118 --> 01:21:43,320 INDIVIDUALS UNDERGOING SURGICAL 1672 01:21:43,320 --> 01:21:47,124 RESECTION OR LOCAL ABLATION WHO 1673 01:21:47,124 --> 01:21:49,693 HAD FEATURES OF HIGH RISK FOR 1674 01:21:49,693 --> 01:21:52,630 REOCCURRENCE WHO UNDERWENT 1675 01:21:52,630 --> 01:21:54,265 THERAPY WITH A MONOCLONAL 1676 01:21:54,265 --> 01:21:56,066 ANTIBODY WERE SHOWN TO HAVE 1677 01:21:56,066 --> 01:21:57,768 SIGNIFICANTLY BETTER OUTCOMES AT 1678 01:21:57,768 --> 01:22:00,905 17 MONTHS COMPARED TO THOSE NOT 1679 01:22:00,905 --> 01:22:02,940 RECEIVING ADJUVANT THERAPY AND 1680 01:22:02,940 --> 01:22:05,476 THEREFORE THE RECOMMENDATION WAS 1681 01:22:05,476 --> 01:22:11,115 TO OFFER ALL PATIENTS ADJUVANT 1682 01:22:11,115 --> 01:22:13,184 THERAPY BUT WITH LONGER TERM 1683 01:22:13,184 --> 01:22:15,085 FOLLOW-UP AND IT SHOWS THE 1684 01:22:15,085 --> 01:22:18,823 IMPORTANCE OF THAT, THE SURVIVAL 1685 01:22:18,823 --> 01:22:19,824 ADVANTAGE DISAPPEARED. 1686 01:22:19,824 --> 01:22:23,594 SUCH THERE WAS NO DIFFERENCE IN 1687 01:22:23,594 --> 01:22:26,664 OUTCOME BETWEEN THE GROUP THAT 1688 01:22:26,664 --> 01:22:30,034 RECEIVED ADJUVANT THERAPY AND 1689 01:22:30,034 --> 01:22:30,201 NOT. 1690 01:22:30,201 --> 01:22:32,903 IN 2025 THE GUIDANCE REVERTED 1691 01:22:32,903 --> 01:22:34,338 BACK TO NOT RECOMMENDING 1692 01:22:34,338 --> 01:22:37,007 ADJUVANT THERAPY FOR RESECTIONAL 1693 01:22:37,007 --> 01:22:37,274 ABLATION. 1694 01:22:37,274 --> 01:22:38,209 I WOULD SAY STAY TUNED. 1695 01:22:38,209 --> 01:22:40,911 BECAUSE WITH IMPROVEMENTS IN 1696 01:22:40,911 --> 01:22:42,513 SYSTEMIC THERAPY, THIS 1697 01:22:42,513 --> 01:22:44,114 RECOMMENDATION IS LIKELY TO BE 1698 01:22:44,114 --> 01:22:49,186 REVISED YET AGAIN. 1699 01:22:49,186 --> 01:22:52,289 ANOTHER QUESTION IS HOW SHOULD 1700 01:22:52,289 --> 01:23:02,833 PATIENTS WITH CIRRHOSIS MANAGE. 1701 01:23:04,568 --> 01:23:06,437 THESE PATIENTS MAY BE ELIGIBLE 1702 01:23:06,437 --> 01:23:08,973 FOR LIVER TRANSPLANTATION BUT 1703 01:23:08,973 --> 01:23:11,141 NOT ELIGIBLE FOR RECEPTION 1704 01:23:11,141 --> 01:23:12,576 POINTS. 1705 01:23:12,576 --> 01:23:13,944 WHILE WAITING ON THE LIST FOR 1706 01:23:13,944 --> 01:23:20,017 LIVER TRANSPLANTATION SHOULD THE 1707 01:23:20,017 --> 01:23:20,684 PATIENTS RECEIVE IMMEDIATE 1708 01:23:20,684 --> 01:23:24,655 ABLATION OR TAKE A WAIT AND SEE 1709 01:23:24,655 --> 01:23:24,922 APPROACH? 1710 01:23:24,922 --> 01:23:28,792 IN GENERAL WHILE ON THE WAIT 1711 01:23:28,792 --> 01:23:32,663 LIST ONLY 10% OF PATIENTS 1712 01:23:32,663 --> 01:23:35,032 EXPERIENCE TUMOR PROGRESSION AND 1713 01:23:35,032 --> 01:23:36,534 THEREFORE THE RECOMMENDATION IS 1714 01:23:36,534 --> 01:23:40,938 CURRENTLY TO TAKE A WAIT AND NOT 1715 01:23:40,938 --> 01:23:47,144 ABLATE APPROACH HOWEVER THEY 1716 01:23:47,144 --> 01:23:50,447 NEED TO RECEIVE IMAGING UNTIL 1717 01:23:50,447 --> 01:23:54,118 TUMOR PROGRESSES TO MORE THAN 2 1718 01:23:54,118 --> 01:23:56,820 CENTIMETERS IN SIZE TO BE 1719 01:23:56,820 --> 01:24:00,424 ELIGIBLE TO RECEIVE ACCEPT 1720 01:24:00,424 --> 01:24:02,393 POINTS AND LISTED FOR LIVER 1721 01:24:02,393 --> 01:24:02,760 TRANSPLANTATION. 1722 01:24:02,760 --> 01:24:07,064 THE ONE EXCEPTION IS THOSE WITH 1723 01:24:07,064 --> 01:24:09,400 ELEVATED ALPHA PROTEIN LEVELS 1724 01:24:09,400 --> 01:24:10,901 AND THEY'RE AT GREATER RISK FOR 1725 01:24:10,901 --> 01:24:12,369 TUMOR PROGRESSION AND THESE 1726 01:24:12,369 --> 01:24:17,141 PATIENTS THE SUBSET OF PATIENTS 1727 01:24:17,141 --> 01:24:21,545 SHOULD RECEIVE IMMEDIATE 1728 01:24:21,545 --> 01:24:26,183 ABLATION. 1729 01:24:26,183 --> 01:24:31,255 ANOTHER DILEMMA IS THOSE AWADING 1730 01:24:31,255 --> 01:24:33,958 LIVER TRANSPLANT RECEIVE 1731 01:24:33,958 --> 01:24:34,191 THERAPY? 1732 01:24:34,191 --> 01:24:38,195 THE IDEA IS WHILE A PATIENT IS 1733 01:24:38,195 --> 01:24:41,098 WAITING DELIVER TRANSPLANTATION 1734 01:24:41,098 --> 01:24:44,401 WE CAN USE THE THERAPY TO 1735 01:24:44,401 --> 01:24:45,536 PREVENT PROGRESSION OF LIVER 1736 01:24:45,536 --> 01:24:47,471 DISEASE WHILE WAITING FOR A 1737 01:24:47,471 --> 01:24:53,143 GRAFT TO BECOME AVAILABLE 1738 01:24:53,143 --> 01:24:53,744 BECAUSE IF PATIENTS PROGRESS 1739 01:24:53,744 --> 01:24:57,481 THEY'RE NO LONGER ELIGIBLE TO 1740 01:24:57,481 --> 01:25:01,885 RECEIVE EXCEPTION POINTS AND MAY 1741 01:25:01,885 --> 01:25:06,657 HAVE TO BE RELISTED AND THE 1742 01:25:06,657 --> 01:25:13,797 CHRIST WAS DEVELOPED TO BENEFIT 1743 01:25:13,797 --> 01:25:16,500 PATIENTS AND IT'S DEFINED AS A 1744 01:25:16,500 --> 01:25:19,370 SINGLE LESION LESS THAN 5 1745 01:25:19,370 --> 01:25:21,739 CENTIMETER IN SIZE OR THREE UP 1746 01:25:21,739 --> 01:25:24,908 TO LESS THAN 3 CENTIMETERS 1747 01:25:24,908 --> 01:25:29,146 WITHOUT VASCULAR INVASION. 1748 01:25:29,146 --> 01:25:30,514 PATIENTS TRANSPLANTED HAVE 1749 01:25:30,514 --> 01:25:33,450 EXCELLENT PROGNOSIS 85% SURVIVAL 1750 01:25:33,450 --> 01:25:34,885 AND THOSE OUTSIDE THE CRITERIA 1751 01:25:34,885 --> 01:25:37,521 HAVE MORE MODERATE SURVIVAL ONLY 1752 01:25:37,521 --> 01:25:47,865 50% FOR FOUR YEARS. 1753 01:25:49,166 --> 01:25:59,643 AND WE HAVE TRANS ARTERIAL CHEMO 1754 01:26:02,012 --> 01:26:06,650 ABLATION AND IT'S BASED ON THE 1755 01:26:06,650 --> 01:26:07,851 UNDERLYING SEVERITY OF THE LIVER 1756 01:26:07,851 --> 01:26:10,354 DISEASE AND PERFORMANCE 1757 01:26:10,354 --> 01:26:11,622 CHARACTERISTICS OF THE 1758 01:26:11,622 --> 01:26:12,823 INDIVIDUAL PATIENT. 1759 01:26:12,823 --> 01:26:23,200 SOME TO BRIDGE ARE THE RISK OF 1760 01:26:23,200 --> 01:26:31,775 HEPATIC COMPENSATION AND NAY 1761 01:26:31,775 --> 01:26:34,611 RECOMMENDED BRIDGING THERAPY FOR 1762 01:26:34,611 --> 01:26:41,218 ALL WITHIN THE CRITERIA AWAITING 1763 01:26:41,218 --> 01:26:42,319 REGARDLESS MUCH WHAT OCCURS 1764 01:26:42,319 --> 01:26:45,522 WHILE WAITING FOR THE LIVER TO 1765 01:26:45,522 --> 01:26:49,159 BECOME AVAILABLE. 1766 01:26:49,159 --> 01:26:56,266 SHOULD PATIENTS OUTSIDE THE 1767 01:26:56,266 --> 01:26:58,502 MILAN CRITERIA BE DOWN GRADED 1768 01:26:58,502 --> 01:27:01,238 AND THE SHORT ANSWER IS YES BUT 1769 01:27:01,238 --> 01:27:02,806 THERE'S MANY CAVEATS. 1770 01:27:02,806 --> 01:27:05,209 THEY'RE THE OPTIMAL FORM OF DOWN 1771 01:27:05,209 --> 01:27:08,145 STAGING THERAPY IS NOT YET 1772 01:27:08,145 --> 01:27:08,412 KNOWN. 1773 01:27:08,412 --> 01:27:10,848 THERE'S NO RECOMMENDED OPTIMAL 1774 01:27:10,848 --> 01:27:12,950 TIME FOR TRANSPLANTATION AFTER 1775 01:27:12,950 --> 01:27:18,555 DOWN STAGING AND NO STANDARDIZED 1776 01:27:18,555 --> 01:27:22,226 CRITERIA OTHER THAN WITHIN THE 1777 01:27:22,226 --> 01:27:29,500 MILAN CRITERIA. 1778 01:27:29,500 --> 01:27:32,369 AND THE MOST WIDELY USED AND 1779 01:27:32,369 --> 01:27:37,775 BEST ARE THE UCF CRITERIA 1780 01:27:37,775 --> 01:27:39,476 ASSOCIATED WITH 81% SURVIVAL. 1781 01:27:39,476 --> 01:27:42,513 SIMILAR TO THAT IN PATIENTS 1782 01:27:42,513 --> 01:27:43,447 WITHIN MILAN CRITERIA AT TIME OF 1783 01:27:43,447 --> 01:27:50,754 LISTING. 1784 01:27:50,754 --> 01:27:53,190 THE ONLY SECTION IS THE INITIAL 1785 01:27:53,190 --> 01:27:56,360 BURDEN EXCEEDING THE MILAN 1786 01:27:56,360 --> 01:27:57,127 CRITERIA THOSE MEETING THE 1787 01:27:57,127 --> 01:27:59,196 CRITERIA SHOULD ALL BE 1788 01:27:59,196 --> 01:28:00,931 CONSIDERED FOR TRANSPLANTATION 1789 01:28:00,931 --> 01:28:02,800 FOLLOWING SUCCESSFUL DOWN 1790 01:28:02,800 --> 01:28:04,401 STAGING TO WITHIN MILAN CRITERIA 1791 01:28:04,401 --> 01:28:09,640 WITHIN A THREE TO SIX MONTH 1792 01:28:09,640 --> 01:28:12,242 PERIOD OF OBSERVATION. 1793 01:28:12,242 --> 01:28:13,343 THE FINAL CONTROVERSIAL ISSUE IS 1794 01:28:13,343 --> 01:28:15,879 WHETHER LOCAL THERAPY IS 1795 01:28:15,879 --> 01:28:18,315 EFFECTIVE FOR PATIENTS WITH 1796 01:28:18,315 --> 01:28:21,118 CIRRHOSIS WITH THAT ARE NOT 1797 01:28:21,118 --> 01:28:24,054 CANDIDATES FOR CURATIVE THERAPY. 1798 01:28:24,054 --> 01:28:27,524 FOR THESE PATIENTS, THE QUESTION 1799 01:28:27,524 --> 01:28:31,195 IS WHETHER THEY'D BENEFIT FROM 1800 01:28:31,195 --> 01:28:33,897 LOCAL REGIONAL THERAPY. 1801 01:28:33,897 --> 01:28:36,733 THERE'S BEEN SEVERAL ANALYSIS 1802 01:28:36,733 --> 01:28:37,768 AND SYSTEMIC REVIEW COMPARING IT 1803 01:28:37,768 --> 01:28:43,740 TO PLACEBO. 1804 01:28:43,740 --> 01:28:47,211 SHOWING VARIABLE RESULTS LIKELY 1805 01:28:47,211 --> 01:28:53,083 BECAUSE OF INHERENT BIASES AND 1806 01:28:53,083 --> 01:28:55,252 LOCAL REGIONAL THERAPY IS 1807 01:28:55,252 --> 01:28:56,820 BENEFICIAL AND THE PROCEDURE OF 1808 01:28:56,820 --> 01:29:01,225 CHOICE IS THERMAL ABLATION RADIO 1809 01:29:01,225 --> 01:29:02,893 FREQUENCY OR MICROWAVE ABLATION 1810 01:29:02,893 --> 01:29:08,332 TO MARK THE PATIENTS WHICH IS 1811 01:29:08,332 --> 01:29:12,502 PREFERRED OR ARTERIAL OR EX TERM 1812 01:29:12,502 --> 01:29:22,813 RADIATION PROTON BEAM THERAPY OR 1813 01:29:22,813 --> 01:29:23,280 CHEMOTHERAPY. 1814 01:29:23,280 --> 01:29:26,984 NOW FOR THE REMAINDER OF THE 1815 01:29:26,984 --> 01:29:37,261 TALK CARCINOMA. 1816 01:29:39,263 --> 01:29:41,331 IN THE LAST TWO DECADES THERE'S 1817 01:29:41,331 --> 01:29:46,603 BEEN SIGNIFICANT ADVANCEMENT IN 1818 01:29:46,603 --> 01:29:53,010 SYSTEMIC THERAPY FOR 1819 01:29:53,010 --> 01:29:56,914 HEPATOSTATIC CARCINOMA AND LATER 1820 01:29:56,914 --> 01:30:04,621 THERE WAS STUD YOZING THE THE 1821 01:30:04,621 --> 01:30:11,328 IMMUNE CHECKPOINT INHIBITERS AND 1822 01:30:11,328 --> 01:30:13,230 THEY HAVE EXPECTED SURVIVAL 1823 01:30:13,230 --> 01:30:13,497 OUTCOMES. 1824 01:30:13,497 --> 01:30:16,900 IN GENERAL THE SURVIVAL OUTCOMES 1825 01:30:16,900 --> 01:30:20,504 WITH SYSTEMIC THERAPY COMPARED 1826 01:30:20,504 --> 01:30:21,305 TO PLACEBO ARE APPROXIMATELY 1827 01:30:21,305 --> 01:30:22,239 THREE TO SIX MONTHS. 1828 01:30:22,239 --> 01:30:31,581 WE USE THE SYSTEMIC THERAPY AND 1829 01:30:31,581 --> 01:30:35,218 WE HAVE THOSE THAT ARE IMMUNE 1830 01:30:35,218 --> 01:30:38,288 CHECKPOINT INHIBITERS AND 1831 01:30:38,288 --> 01:30:41,892 THERE'S MULTI-KINASE INHIBITERS 1832 01:30:41,892 --> 01:30:46,897 AND THOSE OF ANGIOGENESIS AND 1833 01:30:46,897 --> 01:30:49,099 MONOCLONAL ANTIBODIES. 1834 01:30:49,099 --> 01:30:51,368 THE IMMUNE CHECKPOINT INHIBITERS 1835 01:30:51,368 --> 01:30:54,671 THAT PROGRAM DEATH AND THE 1836 01:30:54,671 --> 01:31:04,648 LIGAND AND THERE'S FIRST LINE 1837 01:31:04,648 --> 01:31:08,318 AGENTS EVALUATED IN RANDOMIZED 1838 01:31:08,318 --> 01:31:09,853 CONTROL TRIALS COMPARED TO THE 1839 01:31:09,853 --> 01:31:11,188 STANDARD OF CARE AND SEE IN THE 1840 01:31:11,188 --> 01:31:13,623 FIRST BOX THERE THE MEDIAN OVER 1841 01:31:13,623 --> 01:31:17,361 ALL SURVIVAL RANGES FROM 14 1842 01:31:17,361 --> 01:31:27,704 MONTHS TO 19 MONTHS. 1843 01:31:28,038 --> 01:31:29,539 EXPECTED INCREMENTAL SURVIVAL IS 1844 01:31:29,539 --> 01:31:32,275 THREE TO SIX MONTHS. 1845 01:31:32,275 --> 01:31:35,645 MEDIAN PROGRESSION FREE SURVIVAL 1846 01:31:35,645 --> 01:31:36,947 IS 3 TO 7 MONTHS. 1847 01:31:36,947 --> 01:31:40,817 UNFORTUNATELY THE AGENTS ARE 1848 01:31:40,817 --> 01:31:45,522 ASSOCIATED WITH SIGNIFICANT AND 1849 01:31:45,522 --> 01:31:49,059 SUBSTANTIAL ADVERSE EFFECTS. 1850 01:31:49,059 --> 01:31:52,496 AND WHILE THE AGENT DIFFERS WE 1851 01:31:52,496 --> 01:31:54,598 CAN MAKE GENERALIZATIONS IN THE 1852 01:31:54,598 --> 01:31:56,900 KINASE INHIBITORS ARE ASSOCIATED 1853 01:31:56,900 --> 01:31:59,036 WITH A RASH THAT AFFECT THE 1854 01:31:59,036 --> 01:32:04,241 HANDS AND FEET ASSOCIATED WITH 1855 01:32:04,241 --> 01:32:14,785 WEIGHT LOSS AND FATIGUE AND HAVE 1856 01:32:25,162 --> 01:32:28,265 HIGH RISK OF BLEEDING AND THE 1857 01:32:28,265 --> 01:32:31,001 IMMUNE CHECKPOINT INHIBITORS ARE 1858 01:32:31,001 --> 01:32:32,769 ASSOCIATE WITH IMMUNE RELATED 1859 01:32:32,769 --> 01:32:35,038 ADVERSE EVENTS THAT CAN AFFECT 1860 01:32:35,038 --> 01:32:37,007 ANY BODY SYSTEM BUT 1861 01:32:37,007 --> 01:32:38,442 PREDOMINANTLY THE G.I. TRACT AND 1862 01:32:38,442 --> 01:32:40,911 LIVER AND THYROID COMBLAND. 1863 01:32:40,911 --> 01:32:41,978 -- GLAND. 1864 01:32:41,978 --> 01:32:44,781 BECAUSE OF THESE IMMUNE RELATED 1865 01:32:44,781 --> 01:32:47,317 ADVERSE EVENTS THE INHIBITERS 1866 01:32:47,317 --> 01:32:52,089 ARE CONTRAINDICATED IN PATIENT 1867 01:32:52,089 --> 01:32:55,125 WITH AUTOIMMUNE AND 1868 01:32:55,125 --> 01:32:56,059 CONTRAINDICATED BECAUSE OF THE 1869 01:32:56,059 --> 01:32:57,494 POTENTIAL INCREASED RISK FOR 1870 01:32:57,494 --> 01:33:03,100 GRAPH REJECTION. 1871 01:33:03,100 --> 01:33:06,069 HERE'S A SELECTED SECOND LINE 1872 01:33:06,069 --> 01:33:07,003 STUDIES AFTER FAILURE OF 1873 01:33:07,003 --> 01:33:09,106 TREATMENT. 1874 01:33:09,106 --> 01:33:12,676 AND THE OVER ALL SURVIVAL RANGES 1875 01:33:12,676 --> 01:33:15,879 FROM NINE MONTHS TO 22 MONTHS IN 1876 01:33:15,879 --> 01:33:17,714 THE CHECK MATE TRIAL WHICH 1877 01:33:17,714 --> 01:33:20,817 EVALUATED A COMBINATION OF TWO 1878 01:33:20,817 --> 01:33:29,793 IMMUNE CHECKPOINT AND WE HAVE 1879 01:33:29,793 --> 01:33:30,827 THERAPY AT 22 MONTHS. 1880 01:33:30,827 --> 01:33:33,530 THE RESULT HAS NOT BEEN ABLE TO 1881 01:33:33,530 --> 01:33:36,399 BE REPLICATED IN OTHER STUDIES. 1882 01:33:36,399 --> 01:33:37,968 AND THE COMMON ADVERSE EVENTS 1883 01:33:37,968 --> 01:33:40,504 ASSOCIATED ARE SIMILAR TO THE 1884 01:33:40,504 --> 01:33:46,109 ONES I'VE PREVIOUSLY MENTIONED. 1885 01:33:46,109 --> 01:33:48,512 THIS PUTS IT TOGETHER AND 1886 01:33:48,512 --> 01:33:51,615 SUMMARIZES THE USE OF SYSTEMIC 1887 01:33:51,615 --> 01:33:53,817 AGENTS IN PATIENTS WITH 1888 01:33:53,817 --> 01:33:55,785 UNRESECTABLE HCC. 1889 01:33:55,785 --> 01:33:57,521 THE RECOMMENDED SYSTEMIC THERAPY 1890 01:33:57,521 --> 01:34:01,525 OR APPROACH FOR PATIENTS WITH 1891 01:34:01,525 --> 01:34:06,363 ADVANCED UNRESECTABLE HCC 1892 01:34:06,363 --> 01:34:07,264 IMMUNOTHERAPY IN COMBINATION 1893 01:34:07,264 --> 01:34:17,741 WITH AND MANY PATIENTS HAVE 1894 01:34:21,311 --> 01:34:24,147 CONTRAINDICATIONS LISTED NOTICES 1895 01:34:24,147 --> 01:34:27,384 OF THE SLIDES AND THOSE WITH 1896 01:34:27,384 --> 01:34:28,685 CONTRAINDICATIONS FIRST LINE 1897 01:34:28,685 --> 01:34:35,358 THERAPY WOULD BE WITH ONE OF THE 1898 01:34:35,358 --> 01:34:36,993 MULTI-KINASE INHIBITORS. 1899 01:34:36,993 --> 01:34:38,461 PATIENTS WHO FAIL FIRST LINE 1900 01:34:38,461 --> 01:34:40,597 THERAPY ARE ELIGIBLE TO RECEIVE 1901 01:34:40,597 --> 01:34:44,401 FIRST LINE THERAPY SHOWN IN THE 1902 01:34:44,401 --> 01:34:47,070 BLUE BOX AND SOME MAY BE 1903 01:34:47,070 --> 01:34:48,371 ELIGIBLE FOR THIRD LINE 1904 01:34:48,371 --> 01:34:49,973 TREATMENT OR REFERRED FOR 1905 01:34:49,973 --> 01:34:50,607 EXPERIMENTAL THERAPY IN CLINICAL 1906 01:34:50,607 --> 01:34:55,045 TRIALS. 1907 01:34:55,045 --> 01:35:01,451 SO THAT AN OVERVIEW OF 1908 01:35:01,451 --> 01:35:06,256 MANAGEMENT OF HEPATOSTATIC 1909 01:35:06,256 --> 01:35:07,257 CARCINOMA AND HEALTHY LIFE 1910 01:35:07,257 --> 01:35:08,592 STYLES ARE THE MEASURES TO 1911 01:35:08,592 --> 01:35:11,027 REDUCE HCC RATES. 1912 01:35:11,027 --> 01:35:14,064 SCREENING FOR HEPATOCELLULAR 1913 01:35:14,064 --> 01:35:16,032 CARCINOMA WITH THE PROTEIN IS 1914 01:35:16,032 --> 01:35:17,334 ASSOCIATED WITH IMPROVED 1915 01:35:17,334 --> 01:35:18,635 SURVIVAL AND HAS BEEN SHOWN TO 1916 01:35:18,635 --> 01:35:20,937 BE COST EFFECTIVE AND SHOULD BE 1917 01:35:20,937 --> 01:35:27,944 DONE IN ALL PATIENTS AT RISK FOR 1918 01:35:27,944 --> 01:35:29,012 HEPATOCELLULAR CARCINOMA AND FOR 1919 01:35:29,012 --> 01:35:30,280 THOSE WITH LESIONS THERE'S 1920 01:35:30,280 --> 01:35:33,516 APPROACHES SURGICAL RESECTION, 1921 01:35:33,516 --> 01:35:34,884 TRANSPLANTATION OR ABLATION. 1922 01:35:34,884 --> 01:35:44,661 OUTCOME IS GENERALLY QUITE GOOD. 1923 01:35:44,661 --> 01:35:44,995 FO 1924 01:35:44,995 --> 01:35:50,667 FOR PATIENTS WITH LATE STAGE 1925 01:35:50,667 --> 01:35:51,635 THERAPY ARE ASSOCIATED WITH 1926 01:35:51,635 --> 01:35:54,437 THREE TO SIX MONTHS SURVIVAL 1927 01:35:54,437 --> 01:35:55,605 TIMES COMPARED TO PLACEBO. 1928 01:35:55,605 --> 01:35:57,407 SO THANK YOU SO MUCH FOR YOUR 1929 01:35:57,407 --> 01:35:59,476 ATTENTION AND I'M HAPPY TO TAKE 1930 01:35:59,476 --> 01:36:01,778 QUESTIONS. 1931 01:36:01,778 --> 01:36:03,079 >> THANK YOU. 1932 01:36:03,079 --> 01:36:03,546 THANK YOU VERY MUCH. 1933 01:36:03,546 --> 01:36:12,789 BOTH OF OUR SPEAKERS. 1934 01:36:12,789 --> 01:36:15,992 WE MIGHT BEGIN BY ASKING, SANDY, 1935 01:36:15,992 --> 01:36:17,327 OR MARC DO YOU HAVE QUESTIONS OR 1936 01:36:17,327 --> 01:36:21,865 EACH OTHER AT THIS POINT RELATED 1937 01:36:21,865 --> 01:36:29,339 TO THE TWO PRESENTATIONS ANY 1938 01:36:29,339 --> 01:36:29,572 TAKERS. 1939 01:36:29,572 --> 01:36:34,844 >> MARC, I'M CURIOUS TO KNOW IF 1940 01:36:34,844 --> 01:36:36,079 YOU HAVE A PATIENT PRESENTING 1941 01:36:36,079 --> 01:36:42,919 WITH HCC BUT THE TWO VARIANTS 1942 01:36:42,919 --> 01:36:45,455 BUT DON'T KNOW AND HOW DO MAKE A 1943 01:36:45,455 --> 01:36:50,727 DECISION BEFORE GOING AHEAD ON 1944 01:36:50,727 --> 01:36:51,661 THERAPY? 1945 01:36:51,661 --> 01:36:56,833 >> THANKS FOR THE QUESTION. 1946 01:36:56,833 --> 01:37:01,638 WITH A LA CART RADIO LOGIC 1947 01:37:01,638 --> 01:37:05,408 IMAGING WE CAN DETERMINE THEM 1948 01:37:05,408 --> 01:37:09,079 AND MOST TRY TO AVOID FORMING 1949 01:37:09,079 --> 01:37:14,551 LIVER BIOPSY WHICH IS THE GOLD 1950 01:37:14,551 --> 01:37:22,759 STANDARD BECAUSE OF THE RISK OF 1951 01:37:22,759 --> 01:37:24,961 POTENTIALLY CAUSING METASTASIS. 1952 01:37:24,961 --> 01:37:26,896 MOST CAN BE DIFFERENTIATED WITH 1953 01:37:26,896 --> 01:37:27,797 IMAGING ALONE BUT THERE ARE 1954 01:37:27,797 --> 01:37:32,969 SELECTED CASES WHERE IMAGING IS 1955 01:37:32,969 --> 01:37:35,071 NOT ABLE TO DISTINGUISH BETWEEN 1956 01:37:35,071 --> 01:37:36,639 THE DIFFERENT FORMS AND ONE 1957 01:37:36,639 --> 01:37:38,942 NEEDS TO RELY ON LIVER BIOPSY. 1958 01:37:38,942 --> 01:37:40,677 UNFORTUNATELY THERE'S NO 1959 01:37:40,677 --> 01:37:41,344 BIOMARKERS CURRENTLY AVAILABLE 1960 01:37:41,344 --> 01:37:44,414 TO HELP YOU DISTINGUISH. 1961 01:37:44,414 --> 01:37:49,552 IN THE CASE OF FIBROLAMELLAR 1962 01:37:49,552 --> 01:37:53,123 CARCINOMA ONE CAN LOOK FOR THE 1963 01:37:53,123 --> 01:37:57,527 CHIMERA BUT THERE AREN'T ANY 1964 01:37:57,527 --> 01:38:01,965 BIOMARKERS I'M AWARE. 1965 01:38:01,965 --> 01:38:04,601 >> GO AHEAD, SANDY. 1966 01:38:04,601 --> 01:38:05,535 >> I WAS JUST THANKING HIM FOR 1967 01:38:05,535 --> 01:38:06,936 HIS ANSWER. 1968 01:38:06,936 --> 01:38:07,737 >> THERE'S CONSIDERABLE 1969 01:38:07,737 --> 01:38:10,940 INTEREST, SANDY IN THE 1970 01:38:10,940 --> 01:38:18,815 INVOLVEMENT YOU MENTIONED OF 1971 01:38:18,815 --> 01:38:28,024 XENOBIOTIC METABOLISM AND THE 1972 01:38:28,024 --> 01:38:28,691 TRANSFERASE. 1973 01:38:28,691 --> 01:38:34,330 THIS IS WITHIN THE TUMOR OR IS 1974 01:38:34,330 --> 01:38:37,033 THIS WITHIN THE PART OF THE 1975 01:38:37,033 --> 01:38:37,734 LIVER? 1976 01:38:37,734 --> 01:38:42,972 DO THESE INDIVIDUALS WHO HARBOR 1977 01:38:42,972 --> 01:38:48,211 FIBROLAMELLAR CARCINOMA HAVE A 1978 01:38:48,211 --> 01:38:58,822 DEFECT IN GLUCURONDATION AND 1979 01:39:06,229 --> 01:39:13,069 SOME ARE INNOCUOUS AND THOUGH 1980 01:39:13,069 --> 01:39:16,005 THERE'S A FAMILY OF TRANSFERASES 1981 01:39:16,005 --> 01:39:18,241 THERE'S LITERATURE ON WHAT WE 1982 01:39:18,241 --> 01:39:20,376 CALL MORE CONVENTIONAL 1983 01:39:20,376 --> 01:39:21,511 PHARMACOLOGIC AGENTS. 1984 01:39:21,511 --> 01:39:23,480 DO YOU WANT TO ELABORATE A 1985 01:39:23,480 --> 01:39:26,883 LITTLE BIT MORE, PLEASE ON THIS 1986 01:39:26,883 --> 01:39:37,126 RELATIONSHIP 1987 01:39:41,464 --> 01:39:51,541 >> IN THE CASE OF TICAN IT 1988 01:39:51,541 --> 01:39:52,041 REDRE 1989 01:39:52,041 --> 01:39:52,375 DI 1990 01:39:52,375 --> 01:40:02,852 DEUCES ITS ABILITY AND IT'S 1991 01:40:17,433 --> 01:40:19,202 METABOLIZED TWO OR THREE 1992 01:40:19,202 --> 01:40:21,437 PATHWAYS AND YOU HAVE TO 1993 01:40:21,437 --> 01:40:22,672 IDENTIFY WHAT WERE THE DRUGS 1994 01:40:22,672 --> 01:40:26,309 BEING SOLELY IDENTIFIED BY THOSE 1995 01:40:26,309 --> 01:40:28,745 METABOLIC PATHWAYS AND 1996 01:40:28,745 --> 01:40:31,481 METABOLISM DOWN REGULATED SUCH 1997 01:40:31,481 --> 01:40:33,516 AS THE UDP18 FAMILY OR 634 1998 01:40:33,516 --> 01:40:43,660 FAMILY. 1999 01:40:45,595 --> 01:40:48,231 >> ARE THEY CANCER CELLS? 2000 01:40:48,231 --> 01:40:49,532 >> THERE'S NO CLEAR SIGNS OF 2001 01:40:49,532 --> 01:40:55,738 POLARIZATION ON THEM. 2002 01:40:55,738 --> 01:40:58,341 SO MOST THE TRANSPORTERS SEEK 2003 01:40:58,341 --> 01:40:58,975 THEY'RE NOT EXPRESSED OR NOT 2004 01:40:58,975 --> 01:41:01,644 WHERE THEY SHOULD BE? 2005 01:41:01,644 --> 01:41:07,784 >> ACTUALLY WE HAVE NOT EXAMINED 2006 01:41:07,784 --> 01:41:08,551 THOSE. 2007 01:41:08,551 --> 01:41:10,153 >> WE HAVE ANOTHER QUESTION. 2008 01:41:10,153 --> 01:41:13,623 WHY ARE THE TUMORS LOADED WITH 2009 01:41:13,623 --> 01:41:22,365 FIBROUS TISSUE? 2010 01:41:22,365 --> 01:41:23,166 WE TOOK 2011 01:41:23,166 --> 01:41:26,336 >> WE TOOK PRIMARY HEPATOCYTES 2012 01:41:26,336 --> 01:41:29,706 AND PUT IN THE FUSION GENE AND 2013 01:41:29,706 --> 01:41:38,681 FOUND ALL THE CLASSIC 2014 01:41:38,681 --> 01:41:45,888 TRANSCRIPTS ARE INCREASED OR DIE 2015 01:41:45,888 --> 01:41:47,490 -- DECREASED AS YOU'D EXPECT. 2016 01:41:47,490 --> 01:41:57,867 I'LL GIVE AN EXAMPLE. 2017 01:42:00,503 --> 01:42:02,105 >> IS THIS COMMUNICATION WITH 2018 01:42:02,105 --> 01:42:03,740 THE STELLATE CELLS? 2019 01:42:03,740 --> 01:42:05,775 >> WHEN YOU PUT IN WILD TYPE OR 2020 01:42:05,775 --> 01:42:07,110 FUSION YOU GET ALL THESE CHANGES 2021 01:42:07,110 --> 01:42:09,178 THAT ARE PRETTY MUCH THE SAME. 2022 01:42:09,178 --> 01:42:10,146 THEY GIVE YOU PRETTY MUCH ALL 2023 01:42:10,146 --> 01:42:14,917 THE CHANGES YOU SEE IN 2024 01:42:14,917 --> 01:42:15,451 FIBROLAMELLAR. 2025 01:42:15,451 --> 01:42:16,386 THE ONE EXCEPTION IS COLLAGENS 2026 01:42:16,386 --> 01:42:20,089 WHICH GO DOWN. 2027 01:42:20,089 --> 01:42:21,224 THEY WERE DECREASED. 2028 01:42:21,224 --> 01:42:25,528 SO IF YOU LOOK OVER HERE, THESE 2029 01:42:25,528 --> 01:42:30,166 ARE A SERIES OF CLASSIC MUC13 2030 01:42:30,166 --> 01:42:33,302 TWO UP IN THE PATIENT TUMORS IN 2031 01:42:33,302 --> 01:42:36,439 BLACK AND IN THE PRIMARY 2032 01:42:36,439 --> 01:42:39,208 HEPATOCYTES BY PUTTING IN THE 2033 01:42:39,208 --> 01:42:40,309 TRANSFUSION TRANSCRIPT AND 2034 01:42:40,309 --> 01:42:43,112 COLLAGEN GOES DOWN AND WERE 2035 01:42:43,112 --> 01:42:45,515 CONFUSED WITH THAT AND DID 2036 01:42:45,515 --> 01:42:49,552 SINGLE CELL SPATIAL 2037 01:42:49,552 --> 01:42:50,153 TRANSCRIPTOMICS. 2038 01:42:50,153 --> 01:42:53,489 HERE THE TUMOR CELLS AND IN BLUE 2039 01:42:53,489 --> 01:42:57,527 THE NORMAL AND IN GREEN THE 2040 01:42:57,527 --> 01:43:00,530 STROMAL STELLATE CELLS. 2041 01:43:00,530 --> 01:43:03,933 IT'S IN THE STELLATE CELLS IN 2042 01:43:03,933 --> 01:43:05,301 GREEN, THE WISPY CELLS THEY'RE 2043 01:43:05,301 --> 01:43:07,670 EXPRESSED AND THE COLLAGEN IS 2044 01:43:07,670 --> 01:43:11,307 DECREASED IN THE FIBROLAMELLAR 2045 01:43:11,307 --> 01:43:14,811 CELLS. 2046 01:43:14,811 --> 01:43:17,480 WE HAVE THE RESPONSE TO THE 2047 01:43:17,480 --> 01:43:21,484 FIBROLAMELLAR CELLS. 2048 01:43:21,484 --> 01:43:23,119 >> THERE'S ANOTHER QUESTION THAT 2049 01:43:23,119 --> 01:43:29,058 SPILLS TO YOU, MARC. 2050 01:43:29,058 --> 01:43:34,997 ARE THE TUMORS FIBROLAMELLAR OR 2051 01:43:34,997 --> 01:43:36,432 HEPATOCELLULAR CANCER ARE OFTEN 2052 01:43:36,432 --> 01:43:37,533 DISCOVERED MORE THAN ONE 2053 01:43:37,533 --> 01:43:43,172 KNOWLEDGE -- NODULE OR SO IN THE 2054 01:43:43,172 --> 01:43:43,372 LIVER. 2055 01:43:43,372 --> 01:43:49,545 ARE THOSE SEPARATE ENTITIES OR 2056 01:43:49,545 --> 01:43:50,880 METAST 2057 01:43:50,880 --> 01:43:51,180 METASTASES? 2058 01:43:51,180 --> 01:43:53,883 YOU SHOWED THEY ALL SHOWED THE 2059 01:43:53,883 --> 01:43:57,520 SAME EXTRAORDINARY TRANSCRIPTOME 2060 01:43:57,520 --> 01:43:58,955 BUT HOW DO YOU INTERPRET THAT? 2061 01:43:58,955 --> 01:44:09,365 ARE THOSE LIKELY TO BE 2062 01:44:10,399 --> 01:44:14,937 METASTASES AND FOCAL SITE. 2063 01:44:14,937 --> 01:44:18,274 >> THE BREAK OCCURRING IS VERY 2064 01:44:18,274 --> 01:44:18,508 SLIGHT. 2065 01:44:18,508 --> 01:44:23,379 WE NEVER SEE IT IN SIBLINGS OR 2066 01:44:23,379 --> 01:44:24,013 FAMILY MEMBERS IN THE SAME AREA. 2067 01:44:24,013 --> 01:44:25,515 I THINK IT'S A RARE EVENT. 2068 01:44:25,515 --> 01:44:28,050 IT'S MORE LIKELY TO BE A 2069 01:44:28,050 --> 01:44:30,486 METASTASIS WITHIN THE LIVER BUT 2070 01:44:30,486 --> 01:44:31,621 COULD BE INDEPENDENT. 2071 01:44:31,621 --> 01:44:35,091 SINCE WE DON'T SEE GENETIC 2072 01:44:35,091 --> 01:44:36,459 DIFFERENCES BETWEEN THEM WE 2073 01:44:36,459 --> 01:44:39,195 DON'T HAVE THE DATA TO CLEARLY 2074 01:44:39,195 --> 01:44:41,964 RESULT BETWEEN THE TWO. 2075 01:44:41,964 --> 01:44:43,132 IT'S MORE OF SPECULATION NOT 2076 01:44:43,132 --> 01:44:44,200 SOMETHING WE HAVE GOOD 2077 01:44:44,200 --> 01:44:47,470 EXPERIMENTAL DATA TO RESOLVE ONE 2078 01:44:47,470 --> 01:44:47,870 WAY OR THE OTHER. 2079 01:44:47,870 --> 01:44:49,605 >> MARC, WHAT ABOUT IN THE MORE 2080 01:44:49,605 --> 01:44:52,275 COMMON HCC? 2081 01:44:52,275 --> 01:44:56,612 >> MOST COMMONLY IT PRESENTS AS 2082 01:44:56,612 --> 01:44:59,482 A SOLITARY LESION. 2083 01:44:59,482 --> 01:45:01,517 BUT YOU CAN GET MULTIFOCAL HCC 2084 01:45:01,517 --> 01:45:07,990 AS WELL. 2085 01:45:07,990 --> 01:45:10,126 I THINK MOST ARE CLONAL. 2086 01:45:10,126 --> 01:45:12,428 THE SAME MUTATIONS DRIVING THE 2087 01:45:12,428 --> 01:45:12,929 TUMOR. 2088 01:45:12,929 --> 01:45:15,198 MOST HCC OCCUR IN THE BACKGROUND 2089 01:45:15,198 --> 01:45:17,366 OF CIRRHOSIS AND CIRRHOSIS IS 2090 01:45:17,366 --> 01:45:19,669 CONSIDERED A PREMALIGNANT 2091 01:45:19,669 --> 01:45:21,671 CONDITION AND THAT'S WHY REALLY 2092 01:45:21,671 --> 01:45:24,574 TO PREVENT HCC THE GOAL SHOULD 2093 01:45:24,574 --> 01:45:29,178 BE TO PREVENT CIRRHOSIS FROM 2094 01:45:29,178 --> 01:45:29,478 DEVELOPING. 2095 01:45:29,478 --> 01:45:30,980 CANCERS DEVELOP IN THE ABSENCE 2096 01:45:30,980 --> 01:45:36,018 OF CIRRHOSIS. 2097 01:45:36,018 --> 01:45:38,955 THE ONE EXCESSION IS NOW 2098 01:45:38,955 --> 01:45:42,859 EMERGING AS AN INCREASING CAUSE 2099 01:45:42,859 --> 01:45:45,862 FOR CANCER IN THE ABSENCE OF 2100 01:45:45,862 --> 01:45:46,128 CIRRHOSIS. 2101 01:45:46,128 --> 01:45:49,532 THE OTHER IS HEPATITIS B. 2102 01:45:49,532 --> 01:45:52,802 THAT IS BECAUSE IT CAN DRIVE 2103 01:45:52,802 --> 01:45:54,537 CANCER THROUGH TWO MECHANISMS. 2104 01:45:54,537 --> 01:45:58,474 ONE IS THROUGH THE REPEATED 2105 01:45:58,474 --> 01:46:00,109 INJURY AND REGENERATION THAT 2106 01:46:00,109 --> 01:46:01,010 LEADS TO THE DEVELOPMENT OF 2107 01:46:01,010 --> 01:46:04,180 MUTATIONS TO DRIVE THE CANCER 2108 01:46:04,180 --> 01:46:08,551 AND ALSO REMEMBER IT CAN 2109 01:46:08,551 --> 01:46:11,487 INTEGRATE IN THE HOST GENOME AND 2110 01:46:11,487 --> 01:46:15,258 FIT GENERATES OR TURNS OFF THE 2111 01:46:15,258 --> 01:46:20,062 GENES CAN LEAD TO ONCOGENESIS 2112 01:46:20,062 --> 01:46:22,064 THROUGH A DIFFERENT PATHWAY BUT 2113 01:46:22,064 --> 01:46:26,369 ONLY 20% OF HPV RELATE THE 2114 01:46:26,369 --> 01:46:28,804 CANCERS GROW IN THE ABSENCE OF 2115 01:46:28,804 --> 01:46:29,071 CIRRHOSIS. 2116 01:46:29,071 --> 01:46:32,575 THE MOST OCCUR IN THE CIRRHOTIC 2117 01:46:32,575 --> 01:46:32,875 BACKGROUND. 2118 01:46:32,875 --> 01:46:35,611 >> IN THE ABSENCE OF CIRRHOSIS 2119 01:46:35,611 --> 01:46:37,513 AND I'M THINKING OF THE DAYS 2120 01:46:37,513 --> 01:46:43,452 WHEN THERE WAS A VIRTUAL 2121 01:46:43,452 --> 01:46:47,523 EPIDEMIC OF PRIMARY LIVER CANCER 2122 01:46:47,523 --> 01:46:56,365 IN HEALTHY PEOPLE FROM ZIMBABWE 2123 01:46:56,365 --> 01:47:06,909 AND THEN THERE WAS EVIDENCE THAT 2124 01:47:08,411 --> 01:47:18,654 I WERE EXPOSED TO THINGS LIKE A 2125 01:47:18,654 --> 01:47:21,057 AFLOTOXIN IS THAT STILL A IN 2126 01:47:21,057 --> 01:47:21,590 THOSE WHO HAVE CIRRHOSIS? 2127 01:47:21,590 --> 01:47:31,867 IS IT A FACTOR? 2128 01:47:38,207 --> 01:47:41,510 >> IT'S STILL CONSIDERED A TOXIN 2129 01:47:41,510 --> 01:47:49,552 IN DEVELOPING HEPATOCARCINOMA 2130 01:47:49,552 --> 01:47:53,289 AND THERE WERE WORK SHOWING THAT 2131 01:47:53,289 --> 01:47:57,493 IN TUMOR REPRESSOR GENES. 2132 01:47:57,493 --> 01:48:01,564 NOWADAYS PEANUT MODEL BECAUSE OF 2133 01:48:01,564 --> 01:48:04,333 THE IMPROVEMENT IN STORAGE 2134 01:48:04,333 --> 01:48:05,267 AFLOWTOXIN HAS BEEN REDUCED AND 2135 01:48:05,267 --> 01:48:07,269 IT'S NOT AS SIGNIFICANT FACTOR 2136 01:48:07,269 --> 01:48:17,747 AS MAYBE 30, 40 YEARS AGO. 2137 01:48:17,747 --> 01:48:18,881 THERE ARE OTHER TOXIN THAT CAN 2138 01:48:18,881 --> 01:48:21,550 CONTRIBUTE TO ACC DEVELOPMENT. 2139 01:48:21,550 --> 01:48:30,126 OBESITY IS CLEARLY ONE OF THEM. 2140 01:48:30,126 --> 01:48:31,627 >> WE HAVE SEVERAL QUESTIONS 2141 01:48:31,627 --> 01:48:32,194 WHICH GET DOWN TO THE SAME 2142 01:48:32,194 --> 01:48:38,934 THING. 2143 01:48:38,934 --> 01:48:39,969 THE LIVER CELL NORMALLY LIVES A 2144 01:48:39,969 --> 01:48:49,545 YEAR BEFORE IT DIVIDES. 2145 01:48:49,545 --> 01:48:52,281 IN CIRRHOSIS IS THERE A 2146 01:48:52,281 --> 01:48:53,382 RELATIONSHIP BETWEEN CELLULAR 2147 01:48:53,382 --> 01:48:57,520 TURN OVER AND THE PROPENSITY OF 2148 01:48:57,520 --> 01:49:07,730 MALIGNANCY? 2149 01:49:10,199 --> 01:49:13,436 >> THE LIFE SPAN OF A LIVER CELL 2150 01:49:13,436 --> 01:49:17,506 IS APPROXIMATELY 180 DAYS OR UP 2151 01:49:17,506 --> 01:49:21,510 TO MAYBE A YEAR. 2152 01:49:21,510 --> 01:49:22,945 WITH CHRONIC INFLAMMATION 2153 01:49:22,945 --> 01:49:26,549 TURNOVER OCCURS MORE RAPIDLY AND 2154 01:49:26,549 --> 01:49:33,489 OCCURS IN DAYS OR WEEKS AND 2155 01:49:33,489 --> 01:49:34,123 CONTINUOUS REPEATED BOUTS OF 2156 01:49:34,123 --> 01:49:35,724 NORTH AND REGENERATION CAN LEAD 2157 01:49:35,724 --> 01:49:38,427 TO MUTATIONS THAT CAN THEN DRIVE 2158 01:49:38,427 --> 01:49:45,835 HCC. 2159 01:49:45,835 --> 01:49:49,004 >> WE HAVE ANOTHER QUESTION, 2160 01:49:49,004 --> 01:49:51,707 MARC, AND DO YOU WANT TO SAY 2161 01:49:51,707 --> 01:49:53,509 SOMETHING ABOUT ALPHA FETAL 2162 01:49:53,509 --> 01:49:55,644 PROTEIN AND WHEN IT WAS 2163 01:49:55,644 --> 01:49:57,513 DISCOVERED ALMOST 40 YEARS AGO 2164 01:49:57,513 --> 01:50:06,322 IT ENJOYED A BRIEF MOMENT IN 2165 01:50:06,322 --> 01:50:10,826 FAME IN CANCER GENESIS AND 2166 01:50:10,826 --> 01:50:13,395 DIAGNOSIS AND NOW IT SEEMS AS 2167 01:50:13,395 --> 01:50:15,131 IT'S BEEN RESURRECTED AS THE 2168 01:50:15,131 --> 01:50:15,998 MOST SENSITIVE SCREENING TEST. 2169 01:50:15,998 --> 01:50:17,500 DO YOU WANT TO EXPLAIN MORE 2170 01:50:17,500 --> 01:50:24,140 ABOUT THAT? 2171 01:50:24,140 --> 01:50:25,641 >> IT'S NOT A SENSITIVE MARKER 2172 01:50:25,641 --> 01:50:34,717 OR SPECIFIC. 2173 01:50:34,717 --> 01:50:37,286 COMBINED WITH ULTRASOUND IT HAS 2174 01:50:37,286 --> 01:50:38,287 BETTER SENSITIVITY BUT NOT SO 2175 01:50:38,287 --> 01:50:41,524 MUCH SPECIFICITY UNLESS THE 2176 01:50:41,524 --> 01:50:45,528 LEVEL IS HIGH. 2177 01:50:45,528 --> 01:50:47,396 THE PROBLEM IS A SIGNIFICANT 2178 01:50:47,396 --> 01:50:49,565 PROPORTION OF HCCs DON'T MAKE 2179 01:50:49,565 --> 01:50:53,269 THE PROTEIN PARTICULARLY THE 2180 01:50:53,269 --> 01:50:55,271 WELL DIFFERENT IS THAT IATED TU. 2181 01:50:55,271 --> 01:51:02,011 IT'S A MARKER OF THE IMMATURE 2182 01:51:02,011 --> 01:51:03,812 HEPATOCYTE AND THOSE WELL 2183 01:51:03,812 --> 01:51:04,947 DIFFERENTIATED DON'T MAKE THE 2184 01:51:04,947 --> 01:51:07,349 PROTEIN MAKING IT NOT USEFUL FOR 2185 01:51:07,349 --> 01:51:11,287 DIAGNOSIS OR FOR TRACKING 2186 01:51:11,287 --> 01:51:13,522 OUTCOME FOLLOWING SURGICAL 2187 01:51:13,522 --> 01:51:18,360 RESECTION OR ABLATION. 2188 01:51:18,360 --> 01:51:21,397 THE OTHER ISSUE WITH THE PROTEIN 2189 01:51:21,397 --> 01:51:23,899 IS YOU CAN GET FALSE POSITIVE 2190 01:51:23,899 --> 01:51:27,169 RESULTS BECAUSE DURING BOUTS OF 2191 01:51:27,169 --> 01:51:30,039 REGENERATION IT CAN BE FALSELY 2192 01:51:30,039 --> 01:51:31,473 REGENERATED AND THERE'S OTHER 2193 01:51:31,473 --> 01:51:34,777 TISSUES THAT CAN PRODUCE THE 2194 01:51:34,777 --> 01:51:36,679 PROTEIN WHICH CAN LEAD TO FALSE 2195 01:51:36,679 --> 01:51:41,884 POSITIVES AND LEAD TO A WHOLE 2196 01:51:41,884 --> 01:51:43,719 MASSIVE WORKUP TRYING TO LOOK 2197 01:51:43,719 --> 01:51:50,359 FOR THE CARCINOMA WHEN IT'S 2198 01:51:50,359 --> 01:51:50,593 PRESENT. 2199 01:51:50,593 --> 01:51:57,533 SO IT'S NOT A VERY GOOD 2200 01:51:57,533 --> 01:52:02,805 BIOMARKER BUT ONE OF THE BEST WE 2201 01:52:02,805 --> 01:52:05,107 HAVE AND I WOULD NOT HANG MY HAT 2202 01:52:05,107 --> 01:52:14,850 ON ALPHA BETA PROTEIN. 2203 01:52:14,850 --> 01:52:17,519 >> YOUNG PEOPLE WITH 2204 01:52:17,519 --> 01:52:21,090 FIBROLAMELLAR CANCER DO NOT HAVE 2205 01:52:21,090 --> 01:52:23,626 UNDERLYING CHRONIC LIVER DISEASE 2206 01:52:23,626 --> 01:52:27,296 AND ARE DETECTED AS YOU POINTED 2207 01:52:27,296 --> 01:52:29,231 OUT IN YOUR DAUGHTER'S CASE BY A 2208 01:52:29,231 --> 01:52:37,206 MASS. 2209 01:52:37,206 --> 01:52:39,708 AND SYMPTOMOLOGY IS USUALLY A 2210 01:52:39,708 --> 01:52:44,880 LATE MANIFESTATION NOT AN EARLY 2211 01:52:44,880 --> 01:52:49,818 ONE UNLESS IT'S IN A STRATEGIC 2212 01:52:49,818 --> 01:52:52,454 PLACE IN THE LIVER. 2213 01:52:52,454 --> 01:52:55,624 IS THE PRESENTING COMPLAINT THE 2214 01:52:55,624 --> 01:52:57,326 PATIENT'S PRIMARILY FEEL A MASS 2215 01:52:57,326 --> 01:53:01,196 IN THEIR ABDOMEN OR HOW DO THEY 2216 01:53:01,196 --> 01:53:11,507 COME TO ATTENTION? 2217 01:53:13,609 --> 01:53:18,314 >> IT'S OFTEN DISMISSED IN MY 2218 01:53:18,314 --> 01:53:21,317 DAUGHTER'S TAKE THEY SAID IT WAS 2219 01:53:21,317 --> 01:53:25,020 DUE TO LACTOSE INTOLERANCE AND 2220 01:53:25,020 --> 01:53:28,824 SAID SHE MUST BE CHEATING AND 2221 01:53:28,824 --> 01:53:31,360 YOUNG WOMEN IN THEIR EARLY YEARS 2222 01:53:31,360 --> 01:53:34,029 IT'S A GIRL, IT'S STRESS. 2223 01:53:34,029 --> 01:53:35,631 BUT YOU KNOW YOUR KIDS AT A 2224 01:53:35,631 --> 01:53:36,765 CERTAIN POINT AND IN THIS CASE 2225 01:53:36,765 --> 01:53:38,701 THERE'S ONE THING ON THE SIDE 2226 01:53:38,701 --> 01:53:41,337 AND THERE WAS A SHARP PAIN SO WE 2227 01:53:41,337 --> 01:53:43,172 BROUGHT HER INTO THE 2228 01:53:43,172 --> 01:53:47,042 PEDIATRICIAN, HE SAID OH, IT'S 2229 01:53:47,042 --> 01:53:47,376 APPENDICITIS. 2230 01:53:47,376 --> 01:53:49,578 IT'S BEEN TWO YEARS. 2231 01:53:49,578 --> 01:53:50,679 IT CAN'T BE. 2232 01:53:50,679 --> 01:53:52,381 YOU'RE GOING RIGHT TO THE 2233 01:53:52,381 --> 01:53:54,616 HOSPITAL AND FORTUNATELY THEY 2234 01:53:54,616 --> 01:53:57,553 DID A SCAN AND WHAT THEY SAW WAS 2235 01:53:57,553 --> 01:53:58,654 NOT NOTHING WRONG WITH THE 2236 01:53:58,654 --> 01:54:00,689 APPENDIX BUT MASS IN THE LIVER 2237 01:54:00,689 --> 01:54:03,225 AND SAID IT'S BACTERIAL ABSCESS. 2238 01:54:03,225 --> 01:54:05,828 THEY PUT IN A TUBE TO DRAIN IT 2239 01:54:05,828 --> 01:54:06,428 AND OF COURSE NOTHING DRAINED 2240 01:54:06,428 --> 01:54:09,798 OUT. 2241 01:54:09,798 --> 01:54:13,202 IT'S ESSENTIALLY BEEN 2242 01:54:13,202 --> 01:54:13,836 MISDIAGNOSED IN THESE PATIENTS 2243 01:54:13,836 --> 01:54:14,203 FOR YEARS. 2244 01:54:14,203 --> 01:54:16,205 I'M NOT A CLINICIAN BUT RIGHT 2245 01:54:16,205 --> 01:54:19,441 NOW IN MY RECOMMENDATION WOULD 2246 01:54:19,441 --> 01:54:21,543 BE IF A KID IS COMPLAINING FOR 2247 01:54:21,543 --> 01:54:29,551 AN EXTENDED PERIOD OF TIME ABOUT 2248 01:54:29,551 --> 01:54:32,421 ABDOMINAL ACHES IS AN ULTRASOUND 2249 01:54:32,421 --> 01:54:35,657 AND SEE IF THERE'S A MASS OR NOT 2250 01:54:35,657 --> 01:54:40,796 AND ASSAYS WITH THE TUMOR DNA TO 2251 01:54:40,796 --> 01:54:51,340 PICK UP SIGNS OF THE FUSION DNA. 2252 01:55:02,084 --> 01:55:05,554 >> WHAT ARE THE IDEAS IN THE 2253 01:55:05,554 --> 01:55:07,089 RELATIONSHIP WITH SAY TO CANCER 2254 01:55:07,089 --> 01:55:09,625 IN GENERAL BUT CERTAINLY TO THE 2255 01:55:09,625 --> 01:55:17,533 MORE COMMON HEPATOCELLULAR 2256 01:55:17,533 --> 01:55:27,676 CANCER? 2257 01:55:31,747 --> 01:55:34,316 >> THINGS GET UP REGULATED FOR 2258 01:55:34,316 --> 01:55:35,184 VARIOUS REASONS. 2259 01:55:35,184 --> 01:55:36,685 YOU CARE FUNCTIONALLY WHAT IS 2260 01:55:36,685 --> 01:55:38,220 DRIVING THE TUMOR. 2261 01:55:38,220 --> 01:55:39,354 AND DO A FUNCTIONAL PROVISION 2262 01:55:39,354 --> 01:55:44,626 MEDICINE. 2263 01:55:44,626 --> 01:55:47,663 AND 2264 01:55:47,663 --> 01:55:51,700 >> AND SCREEN AGAINST EVERY DRUG 2265 01:55:51,700 --> 01:55:54,803 TEST AND WHAT IS DRIVING IT. 2266 01:55:54,803 --> 01:55:56,638 IT NOW BECOMES A USEFUL 2267 01:55:56,638 --> 01:55:58,941 THERAPEUTIC AND ONE WAY TO GO IS 2268 01:55:58,941 --> 01:56:01,109 NOT FROM A GENERALIZED 2269 01:56:01,109 --> 01:56:02,978 THERAPEUTIC BUT MUCH MORE 2270 01:56:02,978 --> 01:56:03,612 TARGETED. 2271 01:56:03,612 --> 01:56:07,115 IF IT'S DRIVEN BY FUSION 2272 01:56:07,115 --> 01:56:10,819 PROTEIN, YOU CAN COME UP WITH A 2273 01:56:10,819 --> 01:56:12,888 DEGRADER THAT TARGETS THE 2274 01:56:12,888 --> 01:56:14,456 PROTEIN AND BEYOND CANCER FOR 2275 01:56:14,456 --> 01:56:19,061 PROTEINS MISFOLDS OR AGGREGATED 2276 01:56:19,061 --> 01:56:21,330 WITHIN THE BODY. 2277 01:56:21,330 --> 01:56:22,364 THE TECHNOLOGY AND KNOWLEDGE OF 2278 01:56:22,364 --> 01:56:24,466 THESE TECHNOLOGIES WE DEVELOPED 2279 01:56:24,466 --> 01:56:25,467 I'M VERY FORTUNATE TO DO SCIENCE 2280 01:56:25,467 --> 01:56:28,837 IN A TIME WHEN WE CAN LEARN FROM 2281 01:56:28,837 --> 01:56:30,506 EACH OTHER QUICKLY AND THERE'S 2282 01:56:30,506 --> 01:56:32,441 ALL THESE NEW APPROACHES COMING 2283 01:56:32,441 --> 01:56:34,343 ONLINE NOW AND I THINK THE TERM 2284 01:56:34,343 --> 01:56:35,944 YOU'D SAY IS WE BUILD BRIDGES 2285 01:56:35,944 --> 01:56:38,180 WITH PEOPLE OF DIFFERENT 2286 01:56:38,180 --> 01:56:39,681 DISCIPLINES WHETHER IT'S 2287 01:56:39,681 --> 01:56:40,482 GENOMICS OR ELSEWHERE AND 2288 01:56:40,482 --> 01:56:42,217 TOGETHER WE AS A COMMUNITY NOW 2289 01:56:42,217 --> 01:56:44,720 ARE ABLE TO START APPLYING SOME 2290 01:56:44,720 --> 01:56:49,324 OF THESE PRECISION LESSONS AND 2291 01:56:49,324 --> 01:56:57,132 DEALING WITH OTHER KAERNLSS. 2292 01:56:57,132 --> 01:56:59,535 >> CAN I ASK SANDY A QUESTION, 2293 01:56:59,535 --> 01:57:00,202 IF I MAY? 2294 01:57:00,202 --> 01:57:00,702 >> SURE. 2295 01:57:00,702 --> 01:57:02,804 >> FIRST, THAT WAS A GREAT TALK. 2296 01:57:02,804 --> 01:57:06,241 MY QUESTION IS NOT ONLY HAVE YOU 2297 01:57:06,241 --> 01:57:14,483 PUT TOGETHER THIS PATIENTS WITH 2298 01:57:14,483 --> 01:57:16,184 FIBROLAMELLAR CANCER BUT HAVE 2299 01:57:16,184 --> 01:57:18,620 YOU IDENTIFIED ANY RISK FACTORS 2300 01:57:18,620 --> 01:57:21,957 THAT MIGHT HELP YOU IDENTIFY 2301 01:57:21,957 --> 01:57:26,295 PATIENTS WHO MIGHT BENEFIT FROM 2302 01:57:26,295 --> 01:57:26,562 SCREENING. 2303 01:57:26,562 --> 01:57:29,731 IT'S A RARE CANCER AND TENDS TO 2304 01:57:29,731 --> 01:57:34,469 PRESENT LATE BECAUSE UNTIL THE 2305 01:57:34,469 --> 01:57:36,305 GOES TO A CERTAIN SIZE IT WILL 2306 01:57:36,305 --> 01:57:38,407 BE LARGELY ASYMPTOMATIC. 2307 01:57:38,407 --> 01:57:41,543 MOST THE NERVE ENDINGS ARE IN 2308 01:57:41,543 --> 01:57:44,079 THE CAPSULE AND THERE ISN'T 2309 01:57:44,079 --> 01:57:44,646 NERVE ENDING WESTBOUND THE 2310 01:57:44,646 --> 01:57:51,954 LIVER. 2311 01:57:51,954 --> 01:57:54,089 CAN YOU IDENTIFY RISK FACTORS 2312 01:57:54,089 --> 01:57:55,591 THAT HELP CLINICIANS IDENTIFY 2313 01:57:55,591 --> 01:57:58,193 WHICH PATIENTS MIGHT BE AT RISK 2314 01:57:58,193 --> 01:57:59,728 FOR THIS PARTICULAR TYPE OF 2315 01:57:59,728 --> 01:58:08,804 TUMOR? 2316 01:58:08,804 --> 01:58:10,772 >> MANY PATIENTS ARE CLUSTERED 2317 01:58:10,772 --> 01:58:12,741 TOGETHER IN DIFFERENT PLACES. 2318 01:58:12,741 --> 01:58:15,310 THREE KIDS A FEW BLOCKS WITHIN 2319 01:58:15,310 --> 01:58:17,045 EACH OTHER THERE WAS A DRY 2320 01:58:17,045 --> 01:58:18,347 CLEANER CLOSED BY ENVIRONMENTAL 2321 01:58:18,347 --> 01:58:18,947 PROTECTION AGENCY. 2322 01:58:18,947 --> 01:58:22,551 WE HAVE MANY PEOPLE IN CLUSTERS 2323 01:58:22,551 --> 01:58:24,052 OUTSIDE OF MINNEAPOLIS WITH 2324 01:58:24,052 --> 01:58:25,120 THESE FOREVER CHEMICALS ARE 2325 01:58:25,120 --> 01:58:27,456 BEING DUMPED. 2326 01:58:27,456 --> 01:58:29,858 WE HAVE CLUSTERS TO THE WEST OF 2327 01:58:29,858 --> 01:58:32,127 PHOENIX NOT IN PHOENIX BUT AN 2328 01:58:32,127 --> 01:58:35,697 AREA THAT'S A KNOWN CANCER 2329 01:58:35,697 --> 01:58:40,836 ALLEY. 2330 01:58:40,836 --> 01:58:43,438 IT COULD BE AN ENVIRONMENTAL 2331 01:58:43,438 --> 01:58:46,441 TOXIN BUT DEPENDING ON WHERE IT 2332 01:58:46,441 --> 01:58:49,077 HITS ONE PERSON PRODUCES CANCER 2333 01:58:49,077 --> 01:58:50,612 X AND ANOTHER CANCER J AND THE 2334 01:58:50,612 --> 01:58:52,314 SAME ENVIRONMENTAL TOXIN. 2335 01:58:52,314 --> 01:58:55,951 WE KNOW THERE'S MUTATIONAL 2336 01:58:55,951 --> 01:58:56,318 SIGNATURES. 2337 01:58:56,318 --> 01:58:58,720 WE SEE CLUSTERS OF PATIENTS AND 2338 01:58:58,720 --> 01:59:00,088 WORKING TOGETHER WITH A GROUP 2339 01:59:00,088 --> 01:59:03,558 FROM CHICAGO FORMING THE 2340 01:59:03,558 --> 01:59:06,628 PEDIATRIC CANCER DATA COMMONS TO 2341 01:59:06,628 --> 01:59:10,065 SEE WHICH OTHER CANCERS HAVE 2342 01:59:10,065 --> 01:59:12,467 SIMILAR GEOGRAPHICAL CLUSTERS. 2343 01:59:12,467 --> 01:59:17,539 MY SUSPICION IS IN GENERAL THAT 2344 01:59:17,539 --> 01:59:19,408 PARTICULAR ENVIRONMENTAL TOXIN 2345 01:59:19,408 --> 01:59:21,376 IF THAT'S WHAT IT ENDS UP BEING 2346 01:59:21,376 --> 01:59:23,745 IS A RISK FACTOR FOR DISRUPTING 2347 01:59:23,745 --> 01:59:28,283 THE DNA AND MAY PRODUCE A CANCER 2348 01:59:28,283 --> 01:59:31,420 DEPENDING WHERE IT HITS IN THE 2349 01:59:31,420 --> 01:59:32,788 GENOME. 2350 01:59:32,788 --> 01:59:36,324 WE HAVE TO FIND WHAT'S TRIGGERED 2351 01:59:36,324 --> 01:59:37,826 IT BUT NOT SURE IT'S AN 2352 01:59:37,826 --> 01:59:39,428 APPROPRIATE MARKER FOR 2353 01:59:39,428 --> 01:59:39,695 SCREENING. 2354 01:59:39,695 --> 01:59:44,232 >> WE'RE RUNNING OUT OF TIME BUT 2355 01:59:44,232 --> 01:59:50,238 MARC WE HAVE WHAT IS AN 2356 01:59:50,238 --> 01:59:56,244 INEVITABLE QUESTION OF HOW 2357 01:59:56,244 --> 01:59:59,114 EXPENSIVE IS THE DRUG TREATMENT 2358 01:59:59,114 --> 01:59:59,748 OF HEPATOCELLULAR CANCER AND 2359 01:59:59,748 --> 02:00:03,485 WHAT IS THE QUALITY OF LIFE 2360 02:00:03,485 --> 02:00:05,687 OCCURRING THE PERIOD OF MONTHS 2361 02:00:05,687 --> 02:00:06,722 THAT IN THE OVER ALL LIFE IS 2362 02:00:06,722 --> 02:00:10,559 EXTENDED? 2363 02:00:10,559 --> 02:00:11,760 >> THESE DRUGS ARE OBVIOUSLY NOT 2364 02:00:11,760 --> 02:00:20,135 CHEAP. 2365 02:00:20,135 --> 02:00:22,437 THEY RUN IN THE THOUSANDS OF 2366 02:00:22,437 --> 02:00:32,714 DOLLARS FOR A MONTH OF COST. 2367 02:00:32,714 --> 02:00:33,415 THEY'RE ASSOCIATED WITH SIDE 2368 02:00:33,415 --> 02:00:36,251 WITH QUALITY OF LIFE AND THE 2369 02:00:36,251 --> 02:00:40,288 RASH WITH SOME AND GI HEMORRHAGE 2370 02:00:40,288 --> 02:00:42,190 IF IT OCCURS CAN CONTRIBUTE TO 2371 02:00:42,190 --> 02:00:45,527 THE PATIENT'S DEMISE. 2372 02:00:45,527 --> 02:00:47,763 AND PARTICULARLY WITH THE IMMUNE 2373 02:00:47,763 --> 02:00:49,097 CHECKPOINT INHIBITORS IF YOU 2374 02:00:49,097 --> 02:00:52,067 DEVELOP A COMPLICATION FROM 2375 02:00:52,067 --> 02:00:53,268 THESE IMMUNE RELATED 2376 02:00:53,268 --> 02:00:56,805 COMPLICATIONS THESE CAN BE 2377 02:00:56,805 --> 02:00:58,173 DIFFICULT TO MANAGE AND REQUIRE 2378 02:00:58,173 --> 02:00:59,141 LONG TERM THERAPIES. 2379 02:00:59,141 --> 02:01:03,178 TRYING TO FIND THE BALANCE 2380 02:01:03,178 --> 02:01:05,213 BETWEEN EFFICACY AND SAFETY HAS 2381 02:01:05,213 --> 02:01:07,783 BEEN CHALLENGING. 2382 02:01:07,783 --> 02:01:11,486 I THINK MOVING FORWARD I THINK 2383 02:01:11,486 --> 02:01:14,856 THINGS WILL IMPROVE. 2384 02:01:14,856 --> 02:01:18,727 NOW, IN TERMS OF COST, UNTIL 2385 02:01:18,727 --> 02:01:20,195 THERE'S COMPETITION TO DRIVE 2386 02:01:20,195 --> 02:01:21,630 DOWN COST IT'S PROBABLY NOT 2387 02:01:21,630 --> 02:01:24,633 GOING TO HAPPEN IN THE NEAR 2388 02:01:24,633 --> 02:01:26,635 FUTURE 2389 02:01:26,635 --> 02:01:27,435 >> DO INSURANCE COMPANIES 2390 02:01:27,435 --> 02:01:29,204 GENERALLY COVER THESE COSTS? 2391 02:01:29,204 --> 02:01:29,838 >> IF THEY'RE APPROVED THEY'LL 2392 02:01:29,838 --> 02:01:33,975 COVER THEM. 2393 02:01:33,975 --> 02:01:35,110 >> WELL, LISTEN. 2394 02:01:35,110 --> 02:01:36,444 WE HAVE RUN OUT OF TIME. 2395 02:01:36,444 --> 02:01:39,848 I WANT TO THANK YOU BOTH REALLY 2396 02:01:39,848 --> 02:01:42,984 FOR VERY EXCITING PRESENTATIONS 2397 02:01:42,984 --> 02:01:45,420 ON BOTH SIDES OF THE BRIDGE AND 2398 02:01:45,420 --> 02:01:48,924 I REALLY APPRECIATE BOTH OF YOU 2399 02:01:48,924 --> 02:01:53,862 TAKING THE TIME TO SHARE THE 2400 02:01:53,862 --> 02:01:55,230 EXCITEMENT OF YOUR WORK. 2401 02:01:55,230 --> 02:01:57,432 IT'S GREAT TO SEE YOU BOTH. 2402 02:01:57,432 --> 02:01:59,100 THANKS AGAIN ON BEHALF OF THOSE 2403 02:01:59,100 --> 02:02:00,502 ALL WATCHING AND AROUND THE 2404 02:02:00,502 --> 02:02:04,072 WORLD WHO IF NOT WATCHING TODAY 2405 02:02:04,072 --> 02:02:07,943 WILL SEE THIS THROUGH NIH VIDEO 2406 02:02:07,943 --> 02:02:08,877 ARCHIVE. 2407 02:02:08,877 --> 02:02:09,544 THANK YOU AGAIN FOR SHARING YOUR 2408 02:02:09,544 --> 02:02:13,548 EXCITING WORK. 2409 02:02:13,548 --> 02:02:16,551 >> THANKS FOR THE TALK. 2410 02:02:16,551 --> 02:02:17,886 WIN, THANKS FOR THE INVITATION. 2411 02:02:17,886 --> 02:02:21,223 >> THANK YOU, WIN, FOR THE 2412 02:02:21,223 --> 02:02:21,523 INVITATION. 2413 02:02:21,523 --> 02:02:22,157 HOPE TOO SEE YOU SOON, WIN. 2414 02:02:22,157 --> 02:02:22,390 >> OKAY. 2415 02:02:22,390 --> 02:02:22,457