WALS: The Joy and Impact of Surgical Research

Who speaks in this episode?

• Electron Kebebew (Main speaker)
• Roland Owens (Host)

What is discussed, and when

1. 0:00 – 10:00: Electron Kebebew, NIH, NCI-CCR, Roland Owens
2. 10:00 – 20:00: FDA
3. 20:00 – 30:00: IL13, TCGA
4. 30:00 – 40:00: Anaplastic Thyroid Cancer, IL13, BRAF, MAP Kinase Pathway
5. 40:00 – 50:00: Anaplastic Thyroid Cancer, BRAF
6. 50:00 – 1:00:00: MAP Kinase Pathway, Anaplastic Thyroid Cancer, BRAF, PI3 Kinase Pathway
7. 1:00:00 – 1:02:52: M. D. Anderson

Notable quotes from "WALS: The Joy and Impact of Surgical Research"

• IN 2018, HE MOVED TO STANFORD WHERE HE CONTINUES TO BE AN AMBASSADOR FOR THE NIH INTRAMURAL RESEARCH PROGRAM.

  about NIH · at 2:08

• THE TITLE OF HIS LECTURE TODAY IS THE JOY AND IMPACT OF SURGICAL RESEARCH.

  about Electron Kebebew · at 3:34

• WELL, THERE'S BEEN NO NEW THERAPY APPROVED BY THE FDA IN 6 DECADES.

  about Adrenal Cortical Carcinoma · at 26:12

• THIS FINDING, AT THAT TIME, RAJ POURI WAS AT THE FDA AND HAD AN IL13 PSEUDOEXOITANTS AND CONJUGATED ON IL13 AND MANU JANE EVALUATE IT, THE EXPRESSION OF IL13 ALPHA RECEPTOR 2 IN ADREENA CORTICALE CANCER AND FOUND A.

  about IL13 · at 29:49

• WELL, ALTHOUGH, THERE WERE NO ANAPLASTIC THYROID CANCER SAMPLES ANALYZED IN THE TCGA COHORT, THERE HAVE BEEN REALLY EXCELLENT STUDIES IN USING HIGH THROUGH PUT GENOME SEQUENCING.

  about Anaplastic Thyroid Cancer · at 35:18

• OF THE ANAPLASTIC THYROID CANCER EITHER HAVE A DRIVER MUTATION IN THE MAP KINASE PATHWAY, OR -- AND/OR, THE PI3 KINASE AT KTMTOR PATHWAY WITH A HIGH MUTATION BURDEN.

  about MAP Kinase Pathway · at 37:12

• THE TOP PANEL ACROSS FOR CELL LINES AND THE RED BOX ARE THE BRAF MUTANT ANAPLASTIC THYROID CANCER CELL LINE AS YOU WOULD EXPECT.

  about BRAF · at 45:40

• SHARED WITH YOU 95% OF ANAPLASTIC HAVE ACTIVATION OF BOTH THE MAP AND PI3 KINASE PATHWAY, IS THERE SOMETHING WE CAN'T TARGET?

  about PI3 Kinase Pathway · at 50:44

Who and what is mentioned in this episode?

People

• Electron Kebebew — Person · Main speaker · 3 mentions · first at 0:35
  Featured WALS lecturer presenting on precision surgery, endocrine oncology, and translational research approaches for rare endocrine cancers.
• Roland Owens — Person · Host / introducer · 2 mentions · first at 0:18
  Opens the lecture, provides CME instructions and audience Q&A logistics, and introduces Dr. Kebebew and his credentials; later asks a technical question during Q&A.
  I'M ROLAND OWENS PRINCIPAL DEPUTY DIRECTOR OF INTRAMURAL RESEARCH OFFICE.

Books & papers

• Journal of American Research — Book · Referenced work · 1 mention · first at 4:37
  A journal referenced by Dr. Kebebew in discussing surgical research.
  YOU'RE PROBABLY THINKING WHAT IS SURGICAL RESEARCH AND THIS IS AN ARTICLE BY FRANTIS MOORE, IN THE JOURNAL OF AMERICAN RESEARCH IN 2003 THAT THE HUMAN BODY WILL BENEFIT FROM SURGICAL CARE AND HE DISCOVERED 3 THING,.

Companies & orgs

• NIH — Company · Affiliation · 1 mention · first at 2:13
  National Institutes of Health, where Dr. Kebebew previously worked and continues to collaborate.
• TCGA — Company · Research collaboration · 2 mentions · first at 29:05
  The Cancer Genome Atlas, a project Dr. Kebebew participated in, studying adrenal cancers.
  WELL, WE HAD DONE STUDIES AND THEN THE TCGA STUDY 1 OF THE TARGETS THAT HAD COME OUT WAS IL13 RECEPTOR ALPHA 2.
• NCI-CCR — Company · Affiliation · 1 mention · first at 1:59
  National Cancer Institute - Center for Cancer Research, where Dr. Kebebew was Chief of the Endocrine Oncology Branch.
  FOR THOSE WHO ARE THINKING HE LOOKS FAMILIAR, DR. KEBEBEW SPENT SEVERAL YEARS AT NCI-CCR WHERE HE BECAME THE CHIEF OF THE ENDOCRINE ONCOLOGY BRANCH.
• M. D. Anderson — Company · Referenced institution · 3 mentions · first at 38:05
  Referenced for their work on Anaplastic Thyroid Cancer treatment modalities.
  LOOKINGBACK AT M. D. ANDERSON GROUP'S EXPERIENCE OF BRAF INHIGZITION WHAT'S LEFT IN THE NECK IS ACTUALLY REDIFFERENTIATED TUMOR NAMELY.
• American Thyroid Association — Company · Professional association · 1 mention · first at 3:29
  Professional organization that awarded Dr. Kebebew for his research contributions.
  THYROID, SERVICE ON NUMEROUS NIH REVIEW PANELS AND THE VAN METER AWARD FROM THE AMERICAN THYROID ASSOCIATION FOR OUTSTANDING RESEARCH CONTRIBUTIONS.
• FDA — Company · Regulatory body · 1 mention · first at 19:13
  Mentioned in the context of approving treatments for rare cancers.
  WELL, THERE'S BEEN NO NEW THERAPY APPROVED BY THE FDA IN 6 DECADES.
• California Stem Cell Agency — Company · Funding body · 1 mention · first at 33:03
  Supports the phase 1 trial for CAR T-cell therapy targeting IL13 Receptor Alpha 2.
  HAVE A PHASE 1 TRIAL NOW, OPEN AT 3 INSTITUTIONS, THIS IS SUPPORTED THROUGH THE CALIFORNIA STEM CELL AGENCY, WHERE STANFORD, UCLA AND CITY OF HOPE ARE SITES AND PERSONAL COMMUNICATIONS, HE'S NOT.

Products & tech

• Ludatherapy — Product · Referenced treatment · 1 mention · first at 57:40
  A therapy mentioned in the context of treating neuroendocrine tumors.
  IT'S COMMERCIALLY KNOWN AS LUDATHERAPY ANDA.

Concepts & topics

• Anaplastic Thyroid Cancer — Concept · Core topic · 10 mentions · first at 34:22
  A highly aggressive form of thyroid cancer discussed as a focus of Dr. Kebebew's research.
• BRAF — Concept · Research focus · 5 mentions · first at 37:54
  A gene mutation targeted in the treatment of Anaplastic Thyroid Cancer.
• Adrenal Cortical Carcinoma — Concept · Core topic · 4 mentions
  A rare cancer type discussed by Dr. Kebebew, highlighting the challenges and research in treating it.
• MAP Kinase Pathway — Concept · Research focus · 5 mentions · first at 37:16
  A signaling pathway involved in the progression of Anaplastic Thyroid Cancer.
• IL13 — Concept · Research focus · 4 mentions · first at 29:39
  A receptor targeted in research for treating Adrenal Cortical Carcinoma.
• PI3 Kinase Pathway — Concept · Research focus · 2 mentions · first at 50:47
  Another signaling pathway targeted in Anaplastic Thyroid Cancer research.
• CME — Concept · Professional education · 1 mention · first at 5:55
  Continuing Medical Education credits mentioned at the start of the lecture.
  SO FOR ANY CME CREDIT, THESE ARE MY 2 OBJECTIVES TO SHARE WITH YOU THE ADVANCES AND HOW THIS ALLOWS US TO PROVIDE PERSONALIZED SURGICAL CARE AND.

Full transcript with timestamps

0:16 OKAY, SO WE WILL GET STARTED. GOOD AFTERNOON. WELCOME TO THE WEDNESDAY AFTERNOON LECTURE SERIES. I'M ROLAND OWENS PRINCIPAL DEPUTY DIRECTOR OF INTRAMURAL RESEARCH OFFICE. IT IS MY PLEASURE TO INTRODUCE TODAY'S WALS SPEAKER DR. ELECTRON KEBEBEW WHO MADE REMARKABLE STRIDES IN HIS RESEARCH ON ENDOCRINE TUMORS AND HAS HAD AN OUTSTANDING CAREER AS A MENTOR AND ROLE MODEL TO SURGEON SCIENTISTS AND OTHER TRANSLATIONAL RESEARCHERS. BUT BEFORE I DO, I HAVE 2 VERY QUICK ANNOUNCE WANTS. THE FIRST IS THE CODE FOR CONTINUING MEDICAL EDUCATION CREDITS, THE CODE IS 66818.

1:03 I WILL REPEAT THAT: 66818. ALSO, FOR THOSE WATCHING REMOTELY, YOU CAN SUBMIT QUESTIONS TO THE SPEAKER ANYTIME DURING THIS LECTURE. SIMPLY CLICK THE BUTTON THAT SAYS SEND LIVE FEEDBACK, WHICH IS BELOW THE VIDEOCAST WINDOW. TYPE IN YOUR MESSAGE AND WE WILL RELAY YOUR QUESTION TO THE SPEAKER AT THE END OF THE LECTURE. OKAY. NOW, TO OUR GUEST OF HONOR. DR. ELECTRON KEBEBEW EARNED HIS BS IN CHEMICAL ENGINEERING AT UCLA, AND HIS MD AT UCSF. AFTER COMPLETING A POST DOCTORAL STUDENTAL FELLOWSHIP STUDYING CANCER BIOLOGY AND A GENERAL SURGERY RESIDENCY AT UCSF, HE ROSE TO THE RANK OF ASSOCIATE PROFESSOR.

1:54 FOR THOSE WHO ARE THINKING HE LOOKS FAMILIAR, DR. KEBEBEW SPENT SEVERAL YEARS AT NCI-CCR WHERE HE BECAME THE CHIEF OF THE ENDOCRINE ONCOLOGY BRANCH. IN 2018, HE MOVED TO STANFORD WHERE HE CONTINUES TO BE AN AMBASSADOR FOR THE NIH INTRAMURAL RESEARCH PROGRAM. HE IS CURRENTLY THE CHIEF OF THE DIVISION OF GENERAL SURGERY, AND THE HAIRY A. OBE RHELMAN WALTOR PROFESSOR AT THE STANFORD UNIVERSITY SCHOOL OF MEDICINE. ELECTRON IS AN INTERNATIONALLY RECOGNIZED EXPERT IN ENDOCRINE ONCOLOGY AND SURGERY. HE HAS PERFORMED MORE THAN 5000 OPERATIONS ON THE ADRENAL PARA THYROID AND THYROID GLANDS AND FOR NEWER ENDOSWRIN TUMORS OF THE GASTROINTESTINAL TRACT AND PANCREAS.

2:51 HE HAS OVER 200 INVITED LECTURES AND VISITING PROFESSORSHIPS, ELECTRON AUTHORED ORIGINAL CO AUTHORED OVER 400 SCIENTIFIC ARTICLES, 40 BOOK CHAPTERS OR EDITED OR CO EDITED 4 TEXTBOOKS. HIS SCIENTIFIC CONTRIBUTIONS INCLUDE THE USE OF MOLECULAR MARKERS IN THYROID NODULES TO DEFINE DIAGNOSIS AND PROGNOSIS FOR ENDOCRINE CANCER THERAPY. HIS NUMEROUS AWARDS HONORS AND COMMUNITY SERVICE INCLUDE A STINT AS THE EDITOR AND CHIEF IN THYROID, SERVICE ON NUMEROUS NIH REVIEW PANELS AND THE VAN METER AWARD FROM THE AMERICAN THYROID ASSOCIATION FOR OUTSTANDING RESEARCH CONTRIBUTIONS.

3:34 THE TITLE OF HIS LECTURE TODAY IS THE JOY AND IMPACT OF SURGICAL RESEARCH. PLEASE WELCOME DR. ELECTRON KEBEBEW. [ APPLAUSE ] >> THANK YOU VERY MUCH FOR THAT KIND INTRODUCTION. IT'S WONDERFUL TO BE BACK HERE AT THE BETHESDA CAMPUS. NEVER THOUGHT I WOULD GIVE A WALS LECTURE, I GUESS THAT MEANS I'M GETTING OLDER, BUT REALLY, THANK YOU FOR THE PRIVILEGE OF GIVING THE LECTURE. MY LECTURE TITLE IS VAGUE ON PURPOSE, IT GIVES ME A LICENSE TO TALK ABOUT ANYTHING, RIGHT? THE JOY AND IMPACT OF SURGICAL RESEARCH. SINCE MY DAYS OF BEING THE INTRAMURAL PROGRAM, NOTHING HAS CHANGED, I'M STILL A CIVIL SERVANT AND HAVE NO CONFLICTS TO DECLARE.

4:26 YOU'RE PROBABLY THINKING WHAT IS SURGICAL RESEARCH AND THIS IS AN ARTICLE BY FRANTIS MOORE, IN THE JOURNAL OF AMERICAN RESEARCH IN 2003 THAT THE HUMAN BODY WILL BENEFIT FROM SURGICAL CARE AND HE DISCOVERED 3 THING, DISCOVERY, DEVELOPMENT AND DELIVERY. OF COURSE IN THE MODERN DAY, YOU HAVE TO ASK CHAT GPT, THAT ANSWER WAS WAY TO ALONG FOR ME. IN MY MIND, SURGICAL RESEARCH IS REALLY RESEARCH DONE BY SURGEONS THAT WILL IMPACT PUBLIC HEALTH AND PATIENT OUTCOME. SO A VERY BROAD DEFINITION. PRECISION MEDICINE WE'VE MADE SIGNIFICANT HEAD WAYS.

5:12 MUCH OF THIS THOUGH HAS LOOKED AT PHARMA CO GENOMICS OR PRECISION ONCOLOGY BUT REALLY NONE HAS BEEN WRITTEN ABOUT OR INVESTIGATED ABOUT PRECISION SURGERY AND I'M GOING TO TRY TO SHARE WITH YOU FOR THE FIRST HALF OF MY TALK, EXAMPLES OF PRECISION SURGERY AND HOW THAT'S IMPACTED THE MANAGEMENT OF PATIENTS AND I'M AN ENDOCRINE SURGEON, AND I THINK ENDOCRINE TUMORS ARE THE PROTOTYPICAL EXAMPLE FOR THIS, SO I WILL SHARE WITH YOU SOME OF THE WORK WOE DID AND OTHER VS DONE THAT'S MOVED THIS FORWARD WHERE WE'RE REALLY COULD OFFER OPTIMAL CARE BASED ON THE GENETICS OF THE DISEASE OR ADVANCED IMAGING.

5:55 SO FOR ANY CME CREDIT, THESE ARE MY 2 OBJECTIVES TO SHARE WITH YOU THE ADVANCES AND HOW THIS ALLOWS US TO PROVIDE PERSONALIZED SURGICAL CARE AND THEN THE SECOND HALF WILL FOCUS ON AS A SURGEON IN MY RESEARCH, I FOCUSED IN AREAS WHERE I COULD DO BETTER BECAUSE MY PATIENT'S OUTCOME OR THE PATIENT'S OUTCOME IS NOT GREAT. SO I WILL SHARE WITH YOU WORK WE'VE DONE AND OTHERS ARE DOING IN TRYING TO PROLONG THE LIFE OF PATIENTS WITH RARE CANCERS. SO WHAT IS THIS ABOUT PRECISION SURGERY. WELL, THERE'S BEEN SUCH SIGNIFICANT ADVANCES, WE WERE FORTUNATE ENOUGH WHEN I WAS HERE AND THIS TRANSITIONED TO STAND FORD THAT LOOKED AT THE GENOMEAT LAS PINTAS THAT LOOKED AT THE THYROID CANCER, PARA GANG LIAISONNOMAS AND AKREENAL CANCERS AND THEN TUMORS, ANYWHERE FROM 15% HAVE AN INHERIT BACKGROUND, SO THE ADVENT OF NEXT GENERATION SEQUENCING AND HAVING THAT INFORMATION AT THE POINT OF CARE AND AT THE TIME OF SURGICAL

7:01 CONSULTATION IS IMPORTANT CONSIDERING WHAT SURGICAL MANAGEMENTS THE PATIENT SHOULD HAVE. THE OTHER AREA IS ADVANCED IN IMAGING MODALITIES, BOTH FOR DIAGNOSIS, BETTER STAGING TO DETERMINE THE EXTENT OF DISEASE AND IN SOME CASES THEY DETERMINE THE PROGNOSIS OF THE DISEASE. I WILL SHARE WITH YOU SOME EXAMPLE OF WORKS THAT WE DID AND OTHERS HAVE DONE AS WELL IN THAT DOMAIN. SO TO ME, I THINK WE'RE PRACTICE, IN THE DAY AND AGE WHERE WE CAN BE PRECISE WITH THE SURGICAL INTERVENTION AND ACCURATE IN OUR INTERVENTION AND LAY MAN'S TERM, LET THE CRIME FIT THE BUNNISHMENT BECAUSE AS SURGEONS IT'S ALWAYS IMPORTANT TO REMEMBER, NOTHING IS WITHOUT A PRICE, EVEN THE SIMPLEST PROCEDURE COULD HAVE MORBIDITY OR MORTALITY.

7:57 THE FIRST EXAMPLE I WOULD LIKE TO SHARE WITH YOU AND MEDULARY THYROID CANCER THAT ACCOUNTS FOR A LARGE PERCENTAGE OF THYROID CANCERS. IT WAS DISCOVERED IN 1993 AT WASH OF U IN CAMBRIDGE AND IT'S THE ONLY EXAMPLE I KNOW OF AN INHERITED CANCER SYNDROME WHERE THERE'S A GERM LINE MUTATION IN THE ONCOGENE. FORTUNATELY THERE'S HOT SPOTS WITH THESE CODON MUTATIONS OCCUR AND THERE'S VERY EXACT GENO TYPE,-PHENOTYPE WHERE DEPENDING UPON THE CO DONE MUTATION, THE PATIENT COULD BE ATISK RISK FOR MEDULARY CANCER AND THEN OTHER ITEMS LIKE HYPOTHYROIDISM.

8:40 WELL, DURING THIS TIME I WAS DOING MY RESIDENCY AND DID A COUPLE OF PROPHYLACTIC THYROID ETC. ORDER OF MICRONSYS WITH YOUNG KIDS WITH MY MENTOR WHO LATER BECAME MY COLLEAGUE, DR. CLARK, AND THE THYROID CAME BACK NORMAL THYROID. SHOULD WE HAVE INTERVENED, THEY HAD A RED ONCOGENE MUTATION, NOT ONLY DID WE DO A PROPHYLACTIC THYROID O ME AND I REMEMBER FOLLOWING THIS PATIENT WITH A HYPOCALCEMIA AND MANAGING THE HYPOCALCEMIA THAT RESULT FRIDAY THE OPERATION. WELL, I WROTE THIS UP AND IT WAS SURPRISING TO FIND IN THE LITERATURE THAT 8% IN PATIENTS IN THIS SETTING END UP DEVELOPING LYMPHNODE METASTASIS.

9:32 WE ALSO LOOKED AT THE COHORT WHERE WE FOUND THOSE WITH INHERITED DISEASE LARGELY DUE TO SCREENING AND EARLY GENETIC DETECTION AND EARLY DIAGNOSIS, HAD A MUCH BETTER OVERALL SURVIVAL. SO THE WINDOW TO INTERVENE IS EARLY BECAUSE USUALLY ONCE A PATIENT HAS DEVELOPED CLINICAL DISEASE, AS YOU CAN SEE IN THE SURVIVAL CURVE THERE, YOU RARELY CURE THE PATIENTS. RIGHT ABOUT THIS TIME SURGEONS WERE LOOKING AT THIS, AND DISCOVERED DEPENDING UPON THE TYPE OF CODON MUTATION, THE AGE OR EARLIEST AGE OF ONSET OF MEDULARY THYROID CANCER, FAIRLY INFORMATIVE INFORMATION TELLING US FOR SPECIFIC TYPES OF CO DONE MUTATIONS THAT FOR THOSE IN THE TYROSEEN INTRACELLULAR DOMAIN, YOU SHOULD INTERVENE WITHIN THE YEAR OF BIRTH BECAUSE THEY COULD DEVELOP MEDULARY CANCER AT A VERY YOUNG INCAS AND ALONE COULD WAIT TO 5-6 YEARS OF AGE.

10:39 SO BASED ON THIS INFORMATION NOW, WE ACTUALLY RISK STRATIFY THE TYPE OF CODON MUTATION AND WHEN A PREVENTATIVE THYROID ECTOMY SHOULD BE PERFORMED IN ADDITION TO KNOWING WHICH PATIENTS ARE AT RISK OF DEVELOPING OTHER TUMORS AS A COMPONENT OF THIS INHERITED SYNDROME. BUT NOW WE KNOW FOR CLINICALLY EVIDENT DISEASE THAT THE TUMOR SIZE, ANYTHING OF 1 CENTIMETER AND ELEVATED CALCA TONEIN WILL DICTATE WHETHER WE SHOULD DO A PROPHYLACTIC EMILY NODE DISSECTION IN THE SETTING AND THEN MORE RECENT DATA LOOKING AT THE PLASTIC REACTION IN THE TUMOR ON FROZEN SECTION, IF IT'S NEGATIVE, NONE OF THOSE PATIENTS IN OVER 200 PATIENTS EVALUATED HAD LYMPHNODE METASTASIS.

11:25 SO WE USED THIS INFORMATION TO INFORM OUR SURGICAL INTERVENTION IN OFFERING PROPHYLACTIC LYMPHNODE DISSECTION, ONLY WHEN THESE FACTORS ARE PRESENT. SO TO TAKE YOU BACK TO THE -- WHAT I SHARED WITH YOU WHEN I WAS A PGY2. THESE PATIENTS DIDN'T NEED A CENTRAL LYMPHNODE DISSECTION AND FOR THEIR SPECIFIC TYPE OF MUTATION WE COULD HAVE WAITED UNTIL THE AGE OF 10. SO NOW AS ENDOCRINE SURGEONS, WE USE THE GENETIC INFORMATION BOTH FOR MONITORING AND THEN RECOMMENDING WHEN A PROPHYLACTIC THYROID ECTOMY SHOULD BE PERFORMED. ANOTHER AREA, IS FETAL CHROMA SIGNIFY TELOMERAS AND PARA GANG LIAISONNOMAS, AND MANY OF YOU IN MEDICAL SCHOOL OR RESIDENCY REMEMBER THE RULE OF 10, 10% PEDIATRIC, 10% BILATERAL, 10% EXTRA ADRENAL, 10% METASTATIC AND I HAVE A LINE THROUGH THAT BECAUSE WE KNOW THOSE RATES ACTUALLY DEPEND UPON WHAT TYPE OF GERM LINE MUTATION THE PATIENT HAS.

12:37 SO THE PATIENT HAS AN SGHV MUTATION WELL IT'S A MUCH, MUCH HIGHER RISK OF THEM HAVING METASTATIC OR MALIGNANT TUMORS. AND THIS IS INFORMED US AS FAR AS FEIGNAL HIROL ACE AS WELL AS MASS MUTATION BEING AT HIGH RISK FOR METASTATIC DISEASE AND THEN FOR NEUROFIBROSIS TYPE 1 THE RED GERM LINE MUTATION AND VHL HAVING A VERY, VERY LOW RISK FOR HAVING MALIGNANT DISEASE. OBVIOUSLY, THESE PATIENTS REQUIRE SURGICAL INTERVENTION, IF THEY HAVE A FUNCTIONAL TUMOR OR MASS EFFECT, OR IT IS INVASIVE AND THEY HAVE OTHER SITES OF METASTASIS.

13:21 AS I SAID AND SHARED WITH YOU ALREADY, THE AGE OF ONSET, THE TUMOR SIZE, AND THEN WHETHER THEY'LL HAVE MULTIPLE TUMORS OR MALIGNANT TUMORS IS REALLY DRIVEN BY THE GENETIC BACKGROUND AND THE GROWING LIST THAT I HAVE, OF SUSCEPTIBILITY GENES THAT HAVE BEEN DISCOVERED NOT ALL OF THEM HAVE RECHARACTERIZED THE CLEAR CLINICAL GENO TYPE, PHENOTYPE ASSOCIATION BUT FOR MOST THERE'S FAIRLY GOOD DATA. SO HOW DO WE USE THIS INFORMATION. IT'S IMPORTANT BECAUSE WHEN PATIENTS ARE AT RISK FOR BILATERAL FETAL CHROMA SIGNIFY TELOMERAS, AND THEY HAVE A GERM LINE VHL OR ONCA GENE MUTATION, THAT WE WANT TO AVOID ADRENAL INSUFFICIENT, I'M SORRY, A SURGEON ALWAYS HAVE TO HAVE A VIDEO CLIP AND I DIDN'T CHECK IF MY VIDEO CLIP WAS WORKING BEFORE HAND SO I APOLOGIZE BUT IN THOSE INDIVIDUALS YOU COULD DO A CORTICALE SPARING ADRENAL ECTOMY.

14:27 THE OTHER AREA, THAT -- THAT'S WHAT I NEEDED TO DO -- THE OTHER AREA, IN THE INTEREST OF TIME, I WILL CONTINUE -- THE OTHER AREA IS PH EOCHROMKRIST TELOMERA HAVE SO MANY TARGETS FOR IMAGING. I HAVE A TARGET THERE, WE HAVE UPREGULATION OF GLUTETRANSPORTER, SO MAT O TRANSPORTERS, AND YOU ASK WHAT IS THE BEST MODALITY TO APPROPRIATE LOCALIZE THEIR TUMOR, IF IT'S A PATIENT WITH CANCER, PROASHTLY STAGE THE TUMOR. AND THE FUNCTIONAL IMAGING, ISOTOPES TAKE ADVANTAGE OF THESE CELL SURFACE RECEPTORS, AND THIS IS SOME WORK THAT WAS DONE HERE WHEN I WAS HERE, AND 1 OF THE FEW PLACES THAT IS NIH CLINICAL CENTER WHERE YOU COULD DO SUCH A STUDY OF HEAD-TO-HEAD COMPARISON OF IMAGING STUDIES, AND AS YOU CAN SEE, YOU DON'T HAVE TO BE A NUCLEAR MEDICINE PHYSICIAN, OR RADIOLOGIST.

15:28 IN THIS CASE, THIS IS PATIENTS WITH FETAL CHROMOSIGNIFY TELOMERA PARA GANG LIAISONNOMA, YOU COULD DETECT SITES OF DISEASE MUCH MORE SENSITIVELY WITH DODOTATATE, AND FOLLOWED BY FTG, AND THIS IS THE CASE AS WELL FOR HEAD AND NECK GANG LIAISONNOMAS, WHERE THE DETECTION RATE IS HIGHER THAN FDG-PET. SO CASE IN POINT, 16 YEAR-OLD WOMAN, WE SEE WITH A LEFT PELVIC PARA GLUE MARIOUS OHM AYOU TAKE THE PATIENTS TO THE OPERATING ROOM, THAT'S ALL YOU REMOVE IF YOU DON'T DO FUNCTIONAL IMAGING WITH EITHER FDG PET OR DODOTAPE, BUT IF YOU DO DO IT YOU RECOGNIZE THE PATIENT HAS CONTRA LATERAL PARA GANG LIAISONNOMAS THAT SHOULD BE ADDRESSED AT THE TIME OF THE OPERATION.

16:22 SO WHICH 1S, WE LEARN FROM ANATOMIC IMAGING, HELPS US DETERMINE THE EXTENT OF DISEASE IN WHICH CASE YOU ADDRESS THE DISEASE YOU'VE DETECT INDEED A SINGLE OPERATION OR IF THEY'VE GOT A MALIGNANT TUMOR THEN PATIENT PERHAPS DOES NOT BENEFIT FROM HAVING AN OPERATION. THIS IS JUST DATA, IT'S A LITTLE BIT DATED, BUT FROM 2009, TO 2021, INCLUDES DATA FROM STANFORD AS WELL, SORRY, AND YOU COULD SEE, IF YOU ROUTINELY USE FUNCTIONAL IMAGING STUDIES AND 237 OPERATIONS, 75 WERE OPEN, 162, BUT MANY OF THE OPENS WE ENDED UP FINDING WERE METASTATIC DISEASE, SO 22% OF THE PATIENTS HAD ADDITIONAL SITES OF DISEASE THAT NEEDED TO BE ADDRESSED AT THE TIME OF THE OPERATION.

17:14 AND NOT TOO SKEWED TO A COHORT OF PATIENTS WITH PRIMARILY INHERITED DISEASE, AND SIMILARLY, 14% OF THE PATIENTS THAT HAD NO FAMILY HISTORY, ENDED UP TESTING POSITIVE AND THE EXAMPLES OF VHL RED IS LESS LIKELY PAUSE MOST OF THESE PATIENTS PRESENT WITH MEDULARY THYROID CANCER. WE WERE ABLE TO OFFER THOSE PATIENTS CORTICALE SPARING ADRENALECTOMY. ANOTHER AREA THAT ADVANCED IMAGING HAS MADE A SIGNIFICANT IMPACT THIS, IS ACTUALLY A PROTOCOL, SAMIRA SADOWSKI WROTE AS A CLINICAL FELLOW AND NOW IS A LASKER INVESTIGATOR HERE, IT'S A STUDY THAT YOU CAN DO AT THE NIH CLINICAL CENTER.

18:02 THERE WERE STUDIES THAT WERE PERSPECTIVE OUT OF ROTTER DAM AND BUT NONE IN THE U.S. AND SHE COMPARED HEAD-TO-HEAD A SCAN THAT REALLY BELONGS IN THE HISTORY TEXTBOOK OF MEDICINE, SCAN VERSUS DODOSCAN IN ADDITION TO THE ANATOMIC IMAGING AND I THOUGHT THE RESULTS WERE QUITE SURPRISING. YOU COULD SEE PATIENTS THAT DID NOT HAVE ANY EVIDENCE OF DISEASE ON PREVIOUS SCAN WAS SIGNIFICANTLY HIGHER, SO THESE WERE PATIENTS THAT WERE SYMPTOMATIC WITH CARCINOID TYPE FLUSHING THAT WE'RE ABLE TO DETECT THE DISEASE ON DODOITATE SCANNING AND THEN ALSO IN SOME CASES WHERE PATIENTS WE THOUGHT HAD LOCALIZED DISEASE, POTENTIALLY BENEFIT FROM SURGEERAL INTERVENTION, FOUND THEY HAD METASTATIC DISEASE, SO, LONG ACTING SANDOSTATIN WAS THE TREATMENT BENEFIT TO THEM BUT THEN ALSO IDENTIFYING PATIENTS THAT COULD BENEFIT FROM SURGICAL INTERVENTION.

19:09 WHY IS THIS IMPORTANT? HER STUDY WAS 1 OF THE DATA POINTS THAT THE FDA USED TO PROVE THE NET SPOT TEST WHICH IS NOW COMMERCIALLY AVAILABLE BUT BECAUSE OF THIS STUDY, THE NEW GUIDELINES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS RECOMMENDED THAT THE SCAN THAT COULD BE DOTOITATE AND DOTOKNOCK SHOULD BE PART OF THE INITIAL EVALUATION TO ACRIGHTLY DETERMINE THE EXTENT OF DISEASE. WELL WHEN YOU DO A STUDY, HAVE YOU NEW FINDINGS, YOU END UP GETTING NEW PROBLEMS TO ADDRESS. SOME OF THAT WERE IN PATIENT WHO IS HAD RECURRENT DISEASE, FABULOUS, YOU COULD FIND IT ON THE DOTOITATE SKIN AND THEN YOU HAVE TO GO BACK IN THERE AND RESECT AND YOU COULD SLEEP APNEA AND OBESITY SOME OF THE SITES OF THE DISEASE.

20:00 I HAVE AN EXAMPLE THERE. IT WILL DETECT THINGS THAT ARE 4-MILLIMETER IN SIZE. SO WE ENDED UP SPENDING 6 HOURS TRYING TO LOOK FOR THIS DISEASE AND THEN ASKED THE QUESTION, WELL, WHY DON'T WE GIVE THE ISOTOPE BEFORE THE OPERATION AND USE A GAMMA PROBE AND SEE IF WE COULD BETTER DETECT OR AT LEAST IT'S A BETTER SCAR TISSUE, REMOVE IT AND THEN CHECK THE EXVIVO COUNT TO CONFIRM WE GOT WHAT WE WERE THERE FOR. AND DID THIS IN 44 PATIENTS. PREOPERATIVELY HAD 133 LESIONS, THE TOP EXVIVO, TUMOR TO BACKGROUND RATIO, THAT'S TBR SHOWS THE TUMOR SITES HAD MUCH SIGNIFICANTLY HIGHER ACTIVITY USING THE GAMMA PROBE.

20:53 AND THAT WE FIGURED OUT THE WINDOW FOR THIS WAS IN 3 HOURS. PROBABLY NOT AS IMPORTANT HERE AT THE NIH CLINICAL CENTER, BUT AT STANFORD WHERE I PRACTICE, NOTHING IS GUARANTEED OF WHEN YOU'RE GOING TO GET INTO THE OPERATING ROOM UNLESS YOU'RE THE FIRST CASE START. SO THAT WAS IMPORTANT INFORMATION FOR SURGEONS TO HAVE AND THEN THE MOST IMPORTANT TAKE HOME MESSAGE WAS IN 13% OF THE LESIONS, THEY WERE NOT VISIBLE OR PALPABLE, BUT WE DIDN'T FIND THIS MODALITY REALLY USEFUL FOR PANCREATIC TUMORS AS WELL AS LIVER TUMORS BECAUSE OF THE HIGH CONTROLLER OF BANK GROUND ACTIVITY.

21:34 BUT, THIS COULD ONLY BE USED IN OPEN CASES. THE GROUP FROM MILAN ITALY JUST RECENTLY PUBLISHED THEIR EXPERIENCE AGAIN USING A DODA ISOTOPE IN THAT CASE A DOTATOC, AND EVALUATED IN THIS 20 PATIENTS. THEIR BETA PROBE YOU COULD USE WITH MINIMALLY INVASIVE SURGERY AND PRETTY MUCH CONFIRM THAD WE FOUND THAT THE TUMOR BACKGROUND AND TARGET LESION WAS SIGNIFICANTLY HIGHER AND YOU COULD USE THIS TO DETECT LESION YOU WOULD NOT BE ABLE ON SEE AGAIN, I THINK MOST IMPORTANT IN CASES OF REOPERATIVE CASES, AND THAT USING THE CUT OFF THEY USE FOR THE TUMOR FOR THE BACKGROUND RATIO WAS 1.35-CENTIMETERS, GIVES YOU A RELATIVELY GOOD HIGH ACCURACY RATE.

22:28 NOW I'VE JUST GIVEN YOU 3 XCHS OF ENDOCRINE TUMORS WHERE THE GENETIC BACKGROUND OF THE DISEASE AND ADVANCED IMAGING MODALITIES REALLY HAVE MADE A SIGNIFICANT IMPACT IN HOW WE MANAGE THESE PATIENTS. IN THE INTEREST OF TIME. THAT'S NOT THE ONLY SITE, THIS APPLIES FOR PATIENTS WITH PRIMARY HYPER THYROIDISM AS WELL AND THEN PROBABLY COULD SPEND TALKING ABOUT THE ADVANCES IN THE MANAGEMENT OF THYROID NODULES, MOLECULAR TESTING WERE SICK 95 CANTILY REDUCED THE NEED TO OPERATE ON BENIGN NODULES BY EVALUATING SOMATIC MUTATIONS THAT ARE PRESENT IN THYROID CANCER AS WELL AS ICITATING THE EXTENT OF THYROID ETC. ECTOMY TT WOULD BE NECESSARY.

23:23 BUT I HOPE I CONVINCED YOU AT LEAST IN ENDOCRINE SURGERY WE WERE ABLE TO PRACTICE PRECISE SURGERY BASED ON THE GENETIC BACKGROUND OF THE DISEASE AND ADVANCED IMAGING MODALITIES. NEXT, I WILL TALK ABOUT WORK IN PROGRESS. AND FOR ME, I FOCUSED MUCH OF MY CAREER THE LINE OF THE INVESTIGATION IN AREAS THAT WE COULD DO BETTER, BE IT IN MOLECULAR DIAGNOSTIC FOR THYROIDS. I AM NOT IN THE BUSINESS OF DOING DIAGNOSTIC THYROIDECTOMYS WHEN PATIENTS DON'T NEED IT. SO HAD SOME SUCCESS IN THAT AREA. THE 1 AREA THAT WE'VE AT LEAST I'VE NOT HAD SUCCESS AS AN ENDOCRINE SURGEON IS FOR THE RARE CANCER TYPES AND THAT ISANO PLASTIC THYROID CANCER.

24:18 MUCH OF THIS IS BECAUSE MOST OF THE PATIENTS PRESENT WITH ADVANCED DISEASE BUT MOST INTERESTINGLY THE PATIENT HAD LOCALIZED DISEASE, I'VE NEVER HAD A PATIENT SURVIVE MORE THAN 2 YEARS. SIMILARLY PATIENTS WITH ADRENAL CORTICALE CARCINOMA ALSO PRESENT WITH ADVANCED DISEASE, BUT EVEN WHEN THEY'RE LOCALIZED MORE THAN HALF OF THE PATIENTS AFTER A COMPLETE NEGATIVE MARKER RESECTION END UP HAVING RECURRENT DISEASE. SO WHY STUDY RARE CANCERS? WELL, IT'S PRETTY INTERESTING BECAUSE IT ACCOUNTS FOR ABOUT TWEIVE% OF ALL CANCER DIAGNOSIS, AND -- 27% OF ALL CANCER DIAGNOSIS.

25:03 AND SAME AMOUNT OF MORTALITY, 25%, SO IT'S IMPORTANT FOR THERE TO BE INVESTIGATORS THAT FOCUS ON THIS AREA BUT ALSO RESOURCES TO STUDY THESE CANCERS BECAUSE IN MANY INSTANCES AND I WILL SHARE WITH YOU, FOR ADRENAL CORTICALE CANCER, WHAT WORKS IN COLON CANCER, WHAT WORKS IN LUNG CANCER, IS NOT GOING TO WORK IN ADRENAL CORTICALE CANCER BECAUSE THE BIOLOGY AND THE MODEL CITIZEN LEAKULAR FEATURES AND WHAT DRIVES THE INITIATION OF CORTICALE CANCER IS AMERICAEDLY DIFFERENT. WHY STUDY CANCERS? WHEN YOU LOOK AT THE GAINS THAT HAVE BEEN MADE IN THE SURVIVAL OF SOLID ADULT CANCERS WHERE FROM 57-70% WE'VE NEARLY NOT SEEN THE SAME GAIN FROM RARE CANCERS, ANOTHER REASON TO FOCUS ON STUDYING RARE CANCERS.

26:05 SO WHAT ABOUT ADRENAL CORTICALE CANCER? WELL, THERE'S BEEN NO NEW THERAPY APPROVED BY THE FDA IN 6 DECADES. AS I SHARED WITH YOU MORE THAN 2/3RDS OF PATIENTS PRESENT WITH LOCALLY ADVANCED OR METASTATIC DISEASE AND THIS IS A RANDOMIZED CONTROL TRIAL THE FIRM ACT TRIAL THAT DEFINED WHAT SHOULD BE THE FIRST LINE THERAPY. SO WHAT'S APPROVED FOR ADRENAL CORDICLE CANCER AND THEY COMBINED IT WITH EDM, SIS PLATNIN OR STREPT O SPECIALIZATION OF SPECIFIC ENDOTHELIALIN AND WHAT WENT OUT MIGHT BE COMBINED WITH EDP COMPARED TO MIGHTA DIN STREPTATOSEIN, THE PARTIAL RESPONSE RATE IN THE STUDY WAS 23%, THE COMPLETE RESPONSE RATE WAS 2% AND GUESS WHAT, THAT WAS 2 PATIENTS, BOTH OF WHICH WE HAD A PARTIAL RESPONSE AND THEN SUBSEQUENTLY HAD SURGICAL RESUCTION, SO NOT IN THE TRUE SENSE A COMPLETE RESPONSE.

27:19 AND THEY ALLOWED PATIENTS TO CROSS OVER IF THEY PROGRESSED ON 1 REGIMEN AND FOUND THAT THE OVERALL SURVIVAL OF THE RESPONSE RATE WAS NOT SIGNIFICANTLY DIFFERENT. SO WE CLEARLY NEED TO DO BETTER IN THIS VENUE. WELL, AS I SHARED WITH YOU, WE'VE BEEN FORTUNATE TO PARTICIPATE IN THE CANCER GENOME ATLAS STUDY FOR ADRENAL CANCER AND THIS WAS REALLY IMPORTANT FOR US TO UNDERSTAND WHAT WERE THE DRIVER EVENT, BOTH EPIGENETIC AND GENETIC AS THIS WAS AN INTEGRATED GENOMIC ANALYSIS, OF ADRENAL CANCERS. THE PROBLEM I THOUGHT WITH THIS, AND HAD WHEN WE ARE PARTICIPATING IS WHEN WE WERE LOOKING AT PRIMARY TUMORS AND WE'RE NOT LOOKING AT RECURRENT OR METASTATIC DISEASE WHICH IS REALLY WHAT KILLS PATIENTS.

28:10 LEAVE IT AS IT MAY, THE MAIN FINDINGS FROM THIS ANALYSIS WAS THAT THERE WERE 3 MOLECULAR SUBGROUPS, CLUSTER OF CLUSTERS, THAT WERE RELATED TO PROGNOSIS. WE ALSO UNDERSTOOD THE 4 MAJOR PATHWAYS INVOLVED IN ADRENAL CART CO CARCINOGEN SIS, THAT WAS THE BETA KACCT TINNINE AND CELL CYCLE REGULATORY GENES AND AS WELL AS TRANSCRIPTION FACTORS AND THE PROTEIN KINASE CYCLIC IMP PATHWAY. UNFORTUNATELY, IT'S BEEN DIFFICULT TO TARGET THESE PATHWAYS, IN SOME WAYS ARE NOT TARGETABLE, I THINK WHAT WAS VERY INFORMATIVE IN THIS ANALYSIS IS THE COMPARISON TO 33 DIFFERENT OTHER CANCER TYPES THAT WAS UNDER THE AH SPICES OF THE TCGA STUDY AND IN OVER 10,000 TUMOR SAMPLES AND THAT ADREENA CORTICO CARCINOMA HAD A UNIQUE MODEL UNIQUE -- MOLECULAR PROFILE UNLIKE THE REST OF THE SOLID CANCERS IT WAS COMPARED TO.

29:25 WELL, WE HAD DONE STUDIES AND THEN THE TCGA STUDY 1 OF THE TARGETS THAT HAD COME OUT WAS IL13 RECEPTOR ALPHA 2. IT'S EXPRESSION PROFILES IS REMINISCENT OF A CANCER TESTIS ANTIGEN, SOME OF IT REFERRED TO IT AS A DECOY RECEPTOR, GIVEN THIS FINDING, AT THAT TIME, RAJ POURI WAS AT THE FDA AND HAD AN IL13 PSEUDOEXOITANTS AND CONJUGATED ON IL13 AND MANU JANE EVALUATE IT, THE EXPRESSION OF IL13 ALPHA RECEPTOR 2 IN ADREENA CORTICALE CANCER AND FOUND A HUNDRED PERCENT OF THE SAMPLES WE HAD EXPRESSED MODERATE TO STRONG LEVELS, AND THEN CONDUCTED INVITRO STUDIES AND YOU COULD SEE THERE IN THE BOTTOM PANEL, THE TUMORS ARE COMPLETELY DISRUPTED WHEN THEY'RE TREATED WITH IL13 PSEUDOMOANUS EXOTOXIN AS WELL AS CONDUCTING IN VIVO STUDIES WITH INTER PERO NEAL INJECTIN OF THE IL13 PE WITH SIGNIFICANT TUMOR REGRESSION, THERE AS YOU CAN SEE, UP TO 3 WEEKS AFTER RECEIVING SINGLE DOSE OR SEQUENTIAL DOSES.

30:54 SO WE WERE SUPER EXCITED ABOUT THIS, AND I'M SHARING WITH YOU SOME OF THE STUDIES WE DID HERE, SO, THE TRAINEES, THE FELLOWS IN THE ROOM CAN APPRECIATE WHAT KIND OF SCIENCE YOU COULD DO HERE AND WE'RE ABLE TO TRANSLATE THIS INTO A PHASE 1 TRIAL WHERE WE GAVE SYSTEMIC INTERVENOUS INFUSION OF IL13, PSEUDOMOANUS EXOTOXIN AND PATIENTS THAT HAD UNRECEPTABLE ADRENAL CARCINOMA. NO SURPRISE. MUCH LIKE WE IN THE BIOBANK SPECIMEN ALL PATIENTS HAD STRONG IMMUNOSTAINING FOR IL13 RECEPTOR ALPHA 2. BUT WHEN WE GAVE IT TO THE PATIENTS THAT WERE ENROLLED, FIRST THING YOU NOTICE IS PHARMACOKINETIC STUDIES THAT THE HALF LIFE OF IL13 PE WAS QUITE SHORT.

31:53 WHEN WE DID THE DOSE ESCALATION WENT FROM 1-2 MIKE GRAM PER KILOGRAM THAT WAS THE MAXIMUM TOLERATED DOSE. TWO OUT OF THE 3 PATIENTS AT THAT DOSE ENDED UP DEVELOPING ACUTE RENAL FAILURE, BUT PROBABLY THE MOST IMPORTANT THING IS, 2 OUT OF THE 6 PATIENTS THAT PARTICIPATED ALREADY HAD A NUMERALLIZING ANTIBODY TO IL13 AND THEN THE OTHER 4 PATIENTS THAT GOT INFUSED THEN DEVELOPED NEUTRALIZING ANTIBODIES SO ALTHOUGH VERY, VERY PROMISING, IN PRECLINICAL STUDIES THE RESULTS WERE NEGATIVE. AND THE ERA OF CAR T CELLS ANUSH, CALBASI IS A COLLEAGUE AT STANFORD AND THEY HAVE GENERATED A MUTATED CAR T CELL THAT TARGETS IL13 RECEPTOR ALPHA 2 AND ARE HOPING WILL NOT TARGET ALPHA 1 TO AVOID TOXICITY AND HAVE A PHASE 1 TRIAL NOW, OPEN AT 3 INSTITUTIONS, THIS IS SUPPORTED THROUGH THE CALIFORNIA STEM CELL AGENCY, WHERE STANFORD, UCLA AND CITY OF HOPE ARE SITES AND PERSONAL COMMUNICATIONS, HE'S NOT PRESENTED THIS OR PUBLISHED

33:16 THIS, BUT I WAS EXCITED TO SHARE THIS WITH YOU THAT FIRST PATIENT THAT THAT I HAVE TREATED AS A DRAMATIC RESPONSE TO THIS WITH NO TOXICITY OBSERVED SO I STILL BELIEVE THAT ILRECEPTOR 13 OR ALPHA 2 IS A GREAT THERAPY FOR PATIENTS THAT HAVE UNREFRACTABLE ADRENAL CANCER. NOW I WILL SWITCH OVER TO -- I JUST GOT DONE TELLING YOU HAVE NOT CURED A PATIENT EARLIER THAN 2 YEARS, THIS WAS JUST NCI SEER DATA THAT SHOWS YOU EVEN WHEN PATIENTS HAVE SURGERY, THEIR OVERALL SURVIVAL IS POOR AND THOSE WITHOUT ESSENTIALLY THE MORTALITY RATE IS A HUNDRED% WITHIN A YEAR AND A HALF OF THEM BEING DIAGNOSED.

34:16 IT'S INTERESTING, AND ALTHOUGH IT ONLY ACCOUNTS FOR 1% OF THYROID CANCERS THAT IS ANAPLASTIC THYROID CANCER AND YOU CAN SEE RELATIVE TO ITS LOW INCIDENCE, IT ACCOUNTS FOR NEARLY 2/3RDS OF ALL THYROID CANCER MORTALITYS. SO, IF I WAS FUNDING THYROID CANCER RESEARCH, I WOULD BE FUNDING WHAT'S KILLING PATIENTS. BECAUSE THAT'S REALLY WHAT DRIVES THE REST OF THOSE PATIENTS EITHER HAVE POORLY DIFFERENTIATED THYROID CANCER AND RARELY WELL DIFFERENTIATED METASTATIC THYROID CANCER. SO WHY IS THAT? WELL, ALL ANAPLASTICS ARE STAGED AS STAGE 4 AND AS YOU CAN SEE, EVEN LOCALIZED TUMORS ARE STAGE 4 A AND 4 B BEING LYMPHNODE INVOLVEMENT OR LOCAL INVASION AND THEN 4 C BEING METASTATIC DISEASE.

35:07 AND AS I SHARED WITH YOU, ONLY 10% OF THE PATIENTS ACTUALLY HAVE LOCALIZED DISEASE WHERE IT'S EVEN RESECTABLE. WELL, ALTHOUGH, THERE WERE NO ANAPLASTIC THYROID CANCER SAMPLES ANALYZED IN THE TCGA COHORT, THERE HAVE BEEN REALLY EXCELLENT STUDIES IN USING HIGH THROUGH PUT GENOME SEQUENCING STUDIES TO ANALYZE WHAT THE PRIMARY GENETIC DRIVERS OF ANAPLASTIC THYROID CANCER ARE, AND THIS IS A NICE STUDY THAT ACTUALLY COMPARED IT TO POORLY DIFFERENTIATED THYROID CANCER HERE AND THEN, PATIENTS WHO HAD A FOCUS OF ANAPLASTIC THYROID CANCER, THAT'S MICROSCOPIC DIAGNOSIS AND THEN PATIENTS WITH WIDELY ENFACIVE FOLLICULAR THYROID CANCER AND METASTATIC THYROID CANCER.

36:01 I JUST WANT TO POINT OUT FAYE FEW IMPORTANT THINGS, AS USUALLY THERE'S A FEMALE DISPOSITION FOR POORLY DIFFERENTIATED, WELL DIFFERENTIATED THYROID CANCER, YOU DON'T SEE THAT IN ANAPLASTIC, IT'S ALMOST 50/50. AS I ALREADY SHARED WITH YOU ALMOST ALL PATIENTS HAVE NOT SURVIVED. AND THEN, ADDITIONAL MUTATIONS, CO MUTATIONS ARE EXISTS ANAPLASTICS WHICH SPEAKS TO ITS ORIGIN FROM DIFFERENTIATED THYROID CANCER. WHAT WAS INTERESTING IS EVEN THOUGH IT'S SEWN FORMALLY LETH, THOSE PATIENT WHO IS HAD PROMOTER MUTATIONS HAD A WORSE SURVIVAL TIME AND THEN WHEN YOU LOOK AT WHETHER IT WAS A BRAF OR RAS MUTATION, THOSE ARE THE PATIENTS THAT ALMOST UNIVERSALLY HAD A HUNDRED PERCENT MORTALITY.

37:00 ADDITIONALLY BEYOND THE MORPHOLOGY OF THE CANCER NOW WE'RE ABLE TO ATLAS ALL OF THE MUTATIONS THAT ARE PRESENT AND IN LOOKING AT THIS 95% OR MORE OF THE ANAPLASTIC THYROID CANCER EITHER HAVE A DRIVER MUTATION IN THE MAP KINASE PATHWAY, OR -- AND/OR, THE PI3 KINASE AT KTMTOR PATHWAY WITH A HIGH MUTATION BURDEN. SO, THAT GIVES US NEW TREATMENT OPTIONS ISSUES RIGHT, IN THE NEW WORLD OF DISCOVERING THESE DRIVER MUTATIONS, HAVING SMALL MOLECULES THAT COULD INHIBIT THESE ACTIVATING MUTATIONS AND THE 2 THINGS I HAVE HAD THE RED BOX THERE ARE THINGS THAT HAVE NOW BEEN CLINICALLY APPROVED FOR ANAPLASTIC THYROID CANCER.

37:54 COMBINATION MEK AND BRAF INHIBITION AS WELL AS CHECK POINT ININCREASE INTERNAL AUDIB THORSITTORS AND I WILL SHARE A STUDY BY THE M. D. ANDERSON GROUP THAT GIVES US THE CURRENT STATE OR STATE-OF-THE-ART OF TREATMENT FOR ANAPLASTIC THYROID CANCER WHERE THEY WENT BACK AND LOOKEDDA THE THESE TREATMENT MODALITIES AND WHETHER PATIENTS HAVE BRAF 600 MUTATION AND WHETHER TARGETED THERAPY WAS USED AND WHETHER IMMUNOTHERAPY AND AS YOU CAN SEE WHEN THEY LOOK AT THE COHORT IN THE MOR2017 TO 2019 WHERE THE PATIENTS HAD A BRAF MUTATION, COME BACK AND INHIBITION WITH PDL 1 INHIBITORS THAT THEIR SURVIVAL WAS MUCH BETTER, RIGHT?

38:47 BUT ALMOST ALL OF THESE PATIENTS DEVELOP RESISTANCE, OR TREATMENT RELATED TOXICITY WHERE THEY NEED TO HAVE DOSE REDUCTION OR TREATMENT STOPPAGE. SO ALTHOUGH THE INITIAL RESPONSE IS EXCELLENT AND IN SOME INSTANCES, WE CONSIDER THIS NEW ADJUVANT THERAPY BECAUSE THEY BECOME SURGICAL CANDIDATES, ALMOST EVERY PATIENT, AFTER 2 YEARS HAS RECURRENT DISEASE OR DISEASE PROGRESSION WHERE THAT TARGETED THERAPY IS NOT EFFECTIVE. NOW I'M GOING TO SHARE WITH YOU SOME WORK WE STARTED HERE ACTUALLY. THE 3 THERAPEUTIC STRATEGIES THAT WE HAVE USED 1 WAS TO DO HIGH THROUGH PUT SCREENING, LISA ZANG REMEMBERS THIS, SHE'S BEEN AT THIS FOR 10 + YEARS IN COLLABORATION WITH NCATS WHERE WE SAY, WELL, THE THERAPIES WILL BE DRIVER MUTATION AGNOSTIC AND SCREENED OVER 3000 COMPOUNDS AND THIS WAS AN ATTRACTIVE APPROACH BECAUSE MANY OF THESE DRUGS ARE ALREADY APPROVED FOR SOMETHING OR WERE IN CLINICAL TRIAL WHERE IT COULD LEAD TO EASILY

40:08 EFFICIENT REPURPOSING OF THE DRUG AND THEIR MECHANISM OF ACTION, LARGE PART WAS KNOWN AS WELL AS THEIR TOXICITY PROFILE. BUT, AS MANY OF YOU KNOW, MONOTHERAPY IS NOT LIKELY TO WORK ESPECIALLY IN ANAPLASTIC THYROID CANCER, SO, WHAT WE DID NEXT WAS TAKE THOSE ACTIVE COMPOUNDS AND DO A DRUG MATRIX SCREENING OF 28 DRUGS TO IEE, AUDIENCE DENTIFY WHICH DRUGS MIGHT HAVE A SYNERGISTIC OR ADDITIVE EFFECT, ACROSS THE ANAPLASTIC THYROID CANCER CELL LINES THAT WE HAD SCREENED. WELL, THIS LED US TO IESHES DENTIFY HIGHLY 2 SYNERGISTIC COMPOUNDS, RETOXICITYINIZE AND ARANIFIT, IT'S BEEN IN USE FOR THE LAST 5 DECADES IT'S AN INHIBITOR OF THE PILOT PROJECT RIEWF 8 OXYDACE ENZYME AND THEN AURANOFIN HAS BEEN USED AS A SECOND LINE TREATMENT AND IT INHIBITS THE THIOREDOXIN REDUCT ACE, BOTH OF WHICH CAUSE OXIDATIVE STRESS.

41:21 AND DR. LEE LOOKEDDA THE THIS AND SCROANED BOTH CANCERS WITH THE BRAF MUTATION WILD-TYPE. SHE FOUND SIGNIFICANT SYNERGISTIC EFFECT AS YOU CAN SEE IN THE COMBINATIONS ALMOST COMPLETELY WIPING OUT THE COLONIES AND THE CROSS FOR DIFFERENT CELL LINES AND SIMILARLY USING A PATIENT DERIVED ORGANOID, THIS IS A PATIENT ATC 1, WHO PRESENTED WITH A PRIMARY TUMOR AND NEVER RECEIVED ANY SYSTEMIC THERAPY. BUT WENT ON TO HAVE A BRAF MUTATION AND WAS GIVEN COMBINATION MEK BRAF INHIBITOR AND THEN ATC 2 IS A PATIENT DERIVED XENO GRAPH OR ORGANOID WE DEVELOP FROM A PATIENT THAT RESPONDED EXCEPTIONALLY WELL AND ONLY HAD RESIT SIDUAL LYMPHNODE DISEASE THAT REQUIRED RESECTION, AND YOU CAN SEE IN BOTH EXAMPLES THE ORGANOIDS ARE SIGNIFICANTLY DECREASED OR DESTROYED WITH COMBINATION AND AURANFIN TREATMENT.

42:29 WENT ON TO DO THIS MODEL AND YOU SLEEP APNEA AND OBESITYY IN 2 DIFFERENT CELL LINES THE COMBINATION TREATMENT WAS SIGNIFICANT AND WHAT WAS INTERESTING ABOUT THIS DATA, IS THE TUMOR THAT FORMED A MORE AGGRESSIVE DISEASE ACTUALLY RESPONDED BETTER TO THE COMBINATION TREATMENT THAB THE CELL LINE THAT FORMED LESS AGGRESSIVE DISEASE. SINCE BOTH OF THESE COMPOUNDS ARE IN USE, CLINICALLY, THIS WOULD BE EASY TO TRANSLATE INTO A CLINICAL TRIAL. SHE WENT ON TO LOOK AT THE MECHANISM OF ACTION, INITIALLY WE HAD DONE RNA-SEQ TO LOOK AT EXPRESSION ANALYSIS AND PATHWAYS THAT MIGHT BE INVOLVED BUT WE ENDED UP FINDING THE DRUG MECHANISM OF ACTION DESCRIBED REALLY WHAT WAS AT PLAY HERE WHERE AURANAFFIN INHIBITS GPX4 LEVELSAs WELL AS TRXR THAT LED TO INCREASED INTRACELLULAR ROSS LEVEL ANDS THEN NATIXANIDE WITH AUTOPHAGY AND RESULTED IN ENDOPATHIC RETIC LUMSTRESS WHICH INCREASED THE TOTAL ROSS LEVEL AND THAT'S WHY WE OBSERVED

43:46 SYNERGISTIC ANTICANCER ACTIVITY WHEN WE USED THEM IN COMBINATION. SOPHISTICATEDY WE HOPE TO TRANSLATE THIS INTO A CLINICAL TRIAL THROUGH THE FDA. THE SECOND LINE OF THE 3 THERAPEUTIC STRATEGIES WE'VE USED IS TO LOOK AT WHAT ARE THE RESISTANT TO BRAF INHIBITION PATHWAY THAT HAVE BEEN REPORTED. AND 1 OF THE MECHANISMS THAT'S BEEN RESPORTED IS THIS IS NOT JUST A BRAF IMMUNOTHERAPY RESISTANCE IS THAT THE RESISTA ANT CELLS HAVE A MESENCHYMAL STATE THAT'S DEPENDENT ON GPX 4 AND GPX4 HAS BEEN REPORTED TO BE A GATE KEEPER AND SUPPRESSOR OF FERROPTOSEIS, AND THIS IS ALSO GOOD TO WORK WITH PEOPLE AT STANFORD, THIS HAPPENED TO BE SCOTT DIXON WHO DESCRIBED FERROPTOSIS, IT'S AN IRON DEPENDENTA NONAPOPTOTIC CELL DEATH PATHWAY.

44:53 SO WITH THE TALENT WE THOUGHT THERE, THIS WOULD BE A GOOD OPPORTUNITY TO PURSUE THIS LINE OF INVESTIGATION OF WHETHER TARGETING FERROPTOSIS, COULD LEAD TO MORE EFFECTIVE THERAPY, WITH BRAF. I HAVE THE CARTOON OF THE 2 CANNONICLE PATHWAYS THAT ARE KNOWN PER INTIEWSING FERROPTOSIS, SOMEWHERE THERE'S A KNOWN INHIBITOR OF THIS, ARAFTIN, AND THEN SPECIFIC INHIBITORS OF GPX4, RSL3, AND FIN 56. SO WE LOOKED AT DOING THIS IN COMBINATION WITH BRAF. AND THIS IS DATA THAT I HAVE IN THE TOP PANEL ACROSS FOR CELL LINES AND THE RED BOX ARE THE BRAF MUTANT ANAPLASTIC THYROID CANCER CELL LINE AS YOU WOULD EXPECT.

45:52 THERE'S ABBREVIATED AND SIGNIFICANTLY INHIBITS CELL PROLIFERATION IN THOSE BRAF MUTANT CELL LINE AND THEN TARGETING THE XC-SYSTEM COMPLEX WITH ARASTIN INDUCES SIGNIFICANT CELL DEATH BUT THAT DEATH IS ACTUALLY DIFFERENT IN THAT THE MUTANT IS MORE RESISTANT THAN THE WILD-TYPE. AND THEN WHEN YOU TARGET GPX 4, EITHER USING RSL3 AND THEN ANOTHER COMPOUND ML-162, YOU GET PRETTY MUCH SIGNIFICANT CELL DEATH AND THERE'S NO DIFFERENCE BASED ON THE BRAF MUTATION STATUS. THE LOWER PANEL, FIGURES HERE IS USING THESE 2 COMPOUNDS, SINCE RSL3 HAD A GREAT EFFECT ON INDUCING FERROPTOSIS, WE USED THAT IN COMBINATION OF W-RAFINIB, AND HERE'S SINGLE AGENT RSL3 IN BLUE AND THEN YOU SEE THE COMBINATION AND AGAIN ACROSS ALL 3 CELL LINES, YOU SEE A SYNERGISTIC EFFECT AND THEN THIS JUST PLOTS THE COMBINATION INDEX OF THE DRUGS GENERALLY COMBINATION INDEX OF LESS THAN 1 IS SYNERGISTIC AND THEN AS WE WOULD EXPECT WITH THE BRAF,

47:08 WILD-TYPE, YOU DON'T SEA THAT SYNERGISTIC EFFECT AND SHOULD NOT. HE ALSO DID THIS IN BOTH CELL LINE AND PATIENT DERIVED ORGANOIDS AND THE COMBINATION TREATMENT HERE, TOTALLY DISRUPTED, THE ORGANOIDS, BOTH THE CELL LINE AND PATIENT DERIVED AND THEN WE DID IN VIVO STUDIES AGAIN, THE ORTHOTOPIC MODEL, IN THIS CASE, WE MEASURED THE TUMOR VOLUME AS WELL AS IT HAD THE LUCIFERASE REPORTER IN THE CELL LINE, ASK WHAT YOU SEE HERE THAT FERROPTOSIS INDUCTION WITH THIS IS, C18 WHICH IS A COMPOUND IN DEVELOPMENT FOR CLINICAL USE WITH A MUCH LONGER HALF LIFE THAN RSL3 AND THEN IKEs ALSO AN ARASTIN ANALOGUE THAT TARGETS THE XC COMPLEX TO INDUCE FERROPTOSIS, WHEN BOTH WERE USE INDEED COMBINATION THAT THERE WAS SIGNIFICANT GROWTH INHIBITION COMPARED TO SINGLE DRUG AND THEN SIMILARLY, WHEN MEASURING THE LUMINESCE ENSEL, THE COMBINATION GROUP HAD SIGNIFICANT EFFECT.

48:24 WELL, I ALREADY SHARED WITH YOU, THE REASON WE'RE INTERESTED IN TARGETING FERROPTOSIS IS IT'S BEEN IMPLICATED IN MEDEERATING RESISTANCE AND HE LOOKED AT CELL LINES WE MAINTAINED AND UP TO 40 MICROMOLAR OF RAFANIB, SO HIGHLY RESISTANT AND AS YOU CAN SEE WHEN YOU ADD FERROPTOSIS INDUCTION TO IT, THE CELL LINES, P-PARENTAL AND THEN THE RESISTANT CELL LINE CLONE, AND WHEN YOU ADD RSL 3 TO INHIBIT GPX 4, YOU GET SIGNIFICANT REDUCTION WHILE THE ARASTIN WAS NOT EFFECTIVE. THAT MAKES SENSE BECAUSE RSL3 DIRECTLY TARGETS GPX 4 AND SIMILARLY IN ANOTHER CELL LINE, HERE, WITH SIGNIFICANT SENSITIZATION, BE RAF INHIBITION WHEN YOU ADD RSTHEIR 3 INDUCING FERROPTOSIS, SO THIS HAS PROMISE IN THE SENSE NOT ONLY FOR PRIMARY TREATMENT, BUT ALSO IF THERE'S BRAF RESISTANCE THAT INDUCING FER ROPTOSIS COULD LEAD TO SIGNIFICANT ANTICANCER EFFECT.

49:33 WHEN YOU LOOK AT WHAT THE MECHANISM OF ACTION WAS, IS WE FOUND THAT THE INTRACELLULAR ACCUMULATION OF IRON WAS HIGH AND WHEN YOU LOOKAD THE IMPORTERS OF IRON AND EXPORTER THAT THERE'S DOWN REGULATION OF FERROPOTENT 1 THAT LED TO ENHANCED FENTIN REACTION WITH GENERATION OF ROSS, AND THEN, WHEN MEASURING ROSS OR FBA THAT, LED TO LIPID PEROXIDATION AND WHEN WE LOOK AT SYNERGISTIC EFFECT SIGNIFICANTLY TO ENHANCE FERROPTOSIS ANDOXIDATIVE STRESS WITH LIPID PEROXIDATION, ALL OF THE ASSOCIATED ANTIOXIDANT DEFENSE ACTIVATION THERE WAS PRESENT WITH COMBINATION TREATMENT AS OPPOSE TO SINGLE AGENT.

50:38 LASTLY THE THIRD AREA WE'VE BEEN WORKING ON IS SINCE I ALREADY SHARED WITH YOU 95% OF ANAPLASTIC HAVE ACTIVATION OF BOTH THE MAP AND PI3 KINASE PATHWAY, IS THERE SOMETHING WE CAN'T TARGET? WELL, DUAL TARGETING OF BOTH OF THESE PATHWAYS HAVE BEEN DONE, WHY WAS PDPK1, DEPEND END PROTEIN KINASE 1 SO ATTRACTIVE TO US, WELL, IT WAS DOWN STREAM OF WHERE THE ACTIVATED MUTATION AND THE PI3 KINASE OCCUR, AND IT'S RESPONSIBLE FOR ACTIVATING AKT BY PHOSPHORYLATING IT SO WE THOUGHT THIS WOULD BE BE AN ARK TRACTIVE TARGET AND.

51:22 SECOND REASON IS THERE'S REEL KEEPSAKESLY NO STUDIES IN CANCER WHERE IT'S BEEN TARGETED FOR THERAPY. THE OTHER REASON WE WERE INTERESTED IN AND I SHARED OUR HIGH THROUGH PUT DRUG SCREENING STUDY IN ANAPLASTIC THYROID CANCER AND WHEN WE LOOK AT THE ACTIVE DRUGS FROM THAT SCREENING IN THE CELL LINES, THE TOP PATHWAYS, THAT IS THE ENRICHED PATHWAYS, THAT IS COMPOUNDS THAT WERE REALLY SUPER ACTIVE WERE PI3 KINASE PATHWAY INHIBITOR. SO FOR THAT REASON, WE THOUGHT THAT WOULD BE AN ARK TRACTIVE TARGET TO -- ATTRACTIVE TARGET TO EVALUATE, WE FIRST EVALUATED IT IN CELL LINES AND PHOSPHORYLATED PDPK1 WAS QUITE HIGH IN ALL THE CELL LINES WE ANALYZED AS WELL AS 2 PATIENT DERIVED TUMOR SAMPLES THAT WE HAD HERE.

52:16 SO FOR THAT REASON, WE USED A SMALL MOLECULE INHIBITOR, BX795 TO TARGET INHIBITION OF PHOSPHORYLATION OF PDPK 1. AND THESE ARE 2 CELL LINES THAT ARE BRAF MUTANT HERE AND YOU COULD SEE THAT BX795 EFFECTIVELY INHIBITS THE PHOSPHORYLATION OF PDK1, THAT'S ALSO REFERRED TO AS PDK1 IN BOTH CELL LINES. WHAT WAS INTERESTING IS, WHEN YOU HAVE MONOTHERAPY OR BRAF INHIBITION IN MANY INSTANCES, YOU GET FEEDBACK ACTIVATION OF THE PI3 CAIN ACE PATHWAY, SO HERE IN THE SECOND LANE AS YOU CAN SEE, YOU HAVE UP REGULATION OF FOSTER NURSED FOCUSED ON AKT, AND THEN WHEN YOU DO COMBINATION THERAPY, THAT UPREGULATION IS ATTENUATE AND SIMILARLY WHEN YOU INHIBIT THE PI3 CAIN ACE PATHWAY, LAST COLUMN AND THIRD COLUMN, YOU GET UPREGULATION OF FOSTER NURSED FOCUSED ON MEK, UPREGULATION OF THE MAP KINASE PATHWAY WHICH IS ATTENUATE WITH COMBINATION TREATMENT.

53:30 WHAT WAS EXCITING IS THAT WE FOUND THAT THIS COMBINATION OF INHIBITING PDPK 1 WITH PHOSPHORYLATION WITH BRAF INHIBITION IS IT HA HAD SYNERGISTIC CONFIRMATION AS WELL AS SARKS A -- ASSAYS THAT HE'S RUN ALREADY THAT SHOW THAT THIS COMBINATION WORKS EFFECTIVELY THAN JUST BE RAF INHIBITION ALONE OR PDPK 1 PHOSPHORYLATION ALONE AND HE'S TALKING ABOUT THE MECHANISM, IT LOOKS LIKE IT ENHANCES APOPTOSIS, PRINCIPALLY THROUGH DNA DAMAGE AS WELL AS CAUSING -- WHEN WE LOOK AT CELL CYCLE OR REST, G2 AMARREST, AND ALL THE MARKERS FOR APOPTOSIS, THIS POINTER IS WAY OFF ON ITS OWN WITH COMBINATION TREATMENT, THAT'S CLEAVED PARBCL 2 AS WELL AS CLEAVED CASP A CE 3 ARE INCREASED.

54:37 SOPHISTICATED THIS LOOKS TO BE A PROMISING APPROACH TO BRAF MUTATED ANAPLASTIC THYROID CANCER THAT MAY BE RESISTANT OR MIGHT BE EVEN AS PRIMARY TREATMENT. WA'S LEFT FOR US IS TO IDENTIFY THE OPTIMAL PDPK 1 INHIBITOR TO USE FOR IN VIVO STUDIES THAT HAVE A SIGNIFICANTLY LONG HALF LIFE AND THOSE STUDIES ARE BEING DONE BY DR. PAUL THAT WE HOPE TO USE THIS THEN IN COMBINATION WITH BRAF INHIBITORS. WELL I'VE GIVEN YOU A WORLD WIND AND EXAMPLES OF CLINICAL ADVANCES THAT HAVE LED TO PRECISION SURGERY. AS WELL AS WORK IN PROGRESS, I HOPE I'VE CONVINCED YOU THAT SURGERY IS NOT BARBARISM ANYMORE AND THAT SURGEON SCIENTIST VS SOMETHING TO CONTRIBUTE.

55:35 I WILL JUST FINISH UP WITH A SUMMARY THAT BASED ON THE BETTER BEDDING OF EBD O KRIN AND NEUROENDOCRINE TUMORS AS WELL AS ADVANCED IMAGING MODALITY WE'VE BEEN REALLY ABLE TO IMPACT THE CARE AND MANAGEMENT OF THESE PATIENTS TO AVOID FEUDAL INTERVENTIONS AS WELL AS DETERMINES WHAT THE APPROPRIATE SURGICAL APPROACH AND EXTENT OF RESECTION THAT I BELIEVE HAVE RESULTED IN BETTER OUTCOMES AND I HOPE I'VE GIVEN YOU A FEW EXAMPLES OF WORK WE'VE DONE, OTHERS ARE DOING THAT THERE IS SOME PROMISING AVENUES FOR THE TREATMENT OF RARE CANCERS SPECIFICALLY OOH DREENAL CORTICALE CARCINOMA AND THYROID CANCER AND THEN LASTLY I HOPE YOU BELIEVE SURGEONS HAVE SOMETHING TO CONTRIBUTE IN RESEARCH.

56:21 THANK YOU FOR THE ATTENTION. THESE ARE ALL COLLEAGUES, BOTH AT STANFORD UNIVERSITY, AND FOLKS THAT I STILL COLLABORATE WITH HERE AT THE NIH. LISA ZANG WHO DID MUCH OF THE HIGH THROUGH PUT SCREENING OF THE SMALL MOLECULE COMPOUNDS WITH DR. ZANG AND SHEN AT NCATS AND THEN DR. CHU WHO STILL JOIN US EVERY WEEK AND HAS SMAFORT THINGS TO OFFER OR GROUP. SO THANK YOU FOR GIVING THE ME YOUR ATTENTION AND HAPPY TO ANSWER ANY QUESTIONS YOU MIGHT HAVE. [ APPLAUSE ] >> THANK YOU. PLEASE USE THE MICs, FOR ANY QUESTIONS YOU MIGHT HAVE.

57:03 DR. OWENS YOU SOMETHING HERE, I CAN GIVE YOU THE PRIVILEGE OF USING THE HAND HELD. >> YES I WILL SHOW MY IGNORANCE AND CAN WHAT IS DOTOTATE IS DETECTING? >> YEAH, SORRY, SO IT'S A LIGAND FOR THE SOPHISTICATED MATOSTATIN RECEPTOR. IT'S A THIRD GENERATION THAT HAS HIGH AFFINITY AND SPECIFICALLY BINDS TO SOPHISTICATED MATOSTATIN RECEPTOR 5 AND 2. WHICH ARE EXPRESSED HIGHLY IN NEUROENDOCRINE TUMORS AND FETAL -- GANG LIAISONNOMA, IT'S BEEN EFFECTIVELY USED FOR THERAPY. IT'S COMMERCIALLY KNOWN AS LUDATHERAPY ANDA.

57:44 SO IT'S BEEN USEFUL FOR BOTH DIAGONINOSEIS, DETERMINING THE EXTENT OF DISEASE AND NOW, DEPENDING ON THE RADIO ISOTOPE IT'S BOUND TOO COULD BE USED FOR THERAPY AS WELL. >> PLEASE. >> THANK YOU SO MUCH FOR A BEAUTIFUL LECTURE, AND SHARING WITH US GREAT ACHIEVEMENTS, I HAVE A QUESTION RELATED TO ANAPLASTIC THYROID CANCER AND DURANNAL MEK AND P A/AKT INHIBITION. LOOKINGBACK AT M. D. ANDERSON GROUP'S EXPERIENCE OF BRAF INHIGZITION WHAT'S LEFT IN THE NECK IS ACTUALLY REDIFFERENTIATED TUMOR NAMELY THYROID CANCER SO IN YOUR MODELS HAVE YOU OBSERVED REDIFFERENTIATION MARKERS, DOES IT AFFECT ALSO EXPRESSION OF -- HAVE YOU OBSERVED THIS AS A POTENTIAL AND OTHER PROMISING AVENUE OF MECHANISTIC ACTION OF THIS?

58:49 >> YEAH, THANK YOU FOR THAT VERY INSIGHTFUL QUESTION. YOU KNOW THE REDIFFERENTIATING EFFECT BY INHIBITING THE MAP KINASE PATHWAY, PIK3 HAS BEEN OBSERVED IN INVITRO AS WELL AS ANIMAL MODELS. WE HAVE NOT SPECIFICALLY GONE INTO LOOKING AT THAT AND THE PATHWAYS THAT WE'VE TARGETED AND EVALUATED PART OF IT IS MY FEELING IS THAT THERAPY, THAT WE'RE EVALUATING SHOULD JUST WORK BY ITSELF, ALTHOUGH, I THINK THERE'S A REDIFFERENTIATING EFFECT, YOU'RE PROBABLY FAMILIAR WITH JIM FAGIN'S WORK AND WHAT RESULTED IN A HUGE TRIAL OF YOU INHIBIT THE MAP KINASE PATHWAY, THE SODIUM IODINE EXPORTER EXPRESSION WHICH IS SIM PORTER FOR RADIOACTIVE IBE O DINE WHICH IS VERY EFFECTIVE FOR TREATING THYROID CANCER AND BASED ON HIS OBSERVATION IN PATIENTS WHO USE THAT BOTH WITH RAS OR BRAF MUTATED PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE, PRETTY ROBUST RESPONSE, BUT THEN WE'VE GONE ON AND FOUND THAT IN

1:00:06 THE LARGE TRIAL, THERE'S REALLY NO SIGNIFICANT DIFFERENCE. SO, I THINK THAT -- I HAVE NOT LOOKEDDA THE IT BECAUSE I THINK THAT WHOLE AREA OF INVESTIGATION, YOU NEED TO ACTUALLY CHARACTERIZE WHERE THE NIS, IS, YOU NEED TO CHARACTERIZE THE RETENTION OF THE EYE O DINE AND MY RESEARCH GROUP IS SMALL. SO WE NEED TO FOCUS WHERE INITIALLY THE BIG BANG IS, TO ANSWER YOUR QUESTION, WE HAVEN'T FOCUSED ON IT, BUT I THINK IT'S A VERY EXCELLENT QUESTION THAT ALSO REQUIRES FURTHER INVESTIGATION WHERE THAT REDIFFERENTIATING EFFECT IS ACTUALLY USEFUL FOR THERAPY.

1:00:45 >> THANK YOU SO MUCH. >> I HAVE A QUESTION ONLINE. SIMILAR TO WHAT I ASKED EARLIER TODAY, WHAT ARE THOUGHTS ON THE VALUE OF DAILY BASIS THEA BASES LINKING DATA FROM ELECTRONIC HEALTH RECORDS TO CANCER REGISTRIES TO UNDERSTAND TREATMENT OUTCOMES IN RARE CANCERS? >> YES, I THINK THAT'S EXTREMELY IMPORTANT. I THINK IT'S AN IMPORTANT RESOURCE WITH THE TARGETED THERAPY COMING ONLINE AND OVERALL IMPROVED SURVIVAL THAT'S BEEN REPORTED - BY THE M. D. ANDERSON GROUP, WE WENT BACK TO THE SEER DATA THERE IS NO -- WHEN YOU LOOK ACROSS THE COUNTRY THERE'S NEUROECTODERMAL SIGNIFICANT IMPROVEMENT.

1:01:29 THERE ARE BEGINNING TO BE SOME -- WE HAPPEN TO USE THE EPIC ELECTRONIC MEDICAL RECORDS, AND NOW, THERE'S A PLATFORM WHERE MULTIPLE INSTITUTIONS ARE PARTICIPATING WHERE IT'S PRIMARILY FOR RESEARCH BUT ALLOWS YOU TO ASK IMPORTANT QUESTIONS FOR RARE CANCERS AND THEN ALSO DETERMINE WHETHER THESE TREATMENTS ARE ACTUALLY AVAILABLE AT MOST INSTITUTIONS, SO, YEAH, I THINK IT'S EXTREMELY USEFUL. THERE'S BEGINNING TO BE PLATFORMS TO BE ABLE TO DO THAT BUT THEN AGAIN, I THINK YOU NEED A BIOINFORMATICIAN AND DATA SCIENTIST TO BE ABLE TO ACCESS THIS IS PULL THAT DATA.

1:02:08 >> YEAH, LET ME REPEAT THE CME CODE, IT'S 66818. I WAS HOPING TO ANNOUNCE THE RECEPTION TO BE DELIVERED WITH SURGICAL PRECISION BUT IT HASN'T ARRIVED YET WHICH IS A DRAG BUT MAYBE IF WE TAKE OUR TIME WALKING UP, THINGS WILL CHANGE AND DR. OWENS, YOU HAVE THE FINAL COMMENT. >> THANK YOU EVERYONE, HERE AND IN CYBER WORLD FOR JOINING US. HOPE YOU'LL -- WE DO THIS EVERY WEDNESDAY, SO HOPE YOU CAN BE HERE. [ APPLAUSE ]

Questions about this episode

Who speaks in "WALS: The Joy and Impact of Surgical Research"?

Electron Kebebew (Main speaker), Roland Owens (Host).

What is discussed in "WALS: The Joy and Impact of Surgical Research"?

In order: 0:00 Electron Kebebew, NIH, NCI-CCR, Roland Owens; 10:00 FDA; 20:00 IL13, TCGA; 30:00 Anaplastic Thyroid Cancer, IL13, BRAF, MAP Kinase Pathway; 40:00 Anaplastic Thyroid Cancer, BRAF; 50:00 MAP Kinase Pathway, Anaplastic Thyroid Cancer, BRAF, PI3 Kinase Pathway; 1:00:00 M. D. Anderson.

What is mentioned in this NIH VideoCast episode?

18 people, works and ideas are mentioned, including Electron Kebebew, Anaplastic Thyroid Cancer, BRAF, Adrenal Cortical Carcinoma, MAP Kinase Pathway, IL13. Each one on this page links to its own page with every episode that mentions it.

How long is "WALS: The Joy and Impact of Surgical Research"?

The episode runs 1 h 3 min; the transcript is about 7,606 words in 65 timestamped sections.

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