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>> GOOD AFTERNOON,
EVERYBODY.

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WELCOME TO TODAY'S

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CLINICOPATHOLOGIC GRAND ROUNDS. 

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BEFORE I ANNOUNCE OUR SPEAKERS,

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LET ME JUST ADDRESS A COUPLE OF

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HOUSEKEEPING ISSUES.  FOR THOSE

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WHO REQUIRE CME THE CME CODE FOR

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TODAY'S 57907, YOU KNOW THE

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NUMBER TO TEXT AND IT IS ON THE

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SLIDE THERE SO TEXT THAT CODE

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YOU SHOULD BE ABLE TO RECEIVE

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CME. WE REQUEST THAT YOU PLEASE

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PROVIDE US FEEDBACK AT THE END

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OF THE TALK. YOU CAN DO THAT BY

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SCANNING THE QR CODE THAT WILL

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APPEAR ON THE CME SLIDE AT THE

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END. FOR THOSE WHO APPLIED FOR

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CME YOU WILL GET AN EMAIL LINK

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TO TAKE YOU BACK TO YOUR

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FEEDBACK FORM. WE APPRECIATE

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HEARING FROM YOU. AFTER THE

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PRESENTATION, IF YOU HAVE ANY

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QUESTIONS PLEASE PROCEED FOR

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THOSE IN THE LIVE AUDIENCE

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PROCEED TO THE MIKES IN THE

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AISLES AND FOR THOSE WHO ARE

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VIEWING ONLINE YOU CAN SEND US

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QUESTIONS THROUGH THE LIVE

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FEEDBACK BUTTON AND WE WILL TRY

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TO ADDRESS THEM AS TIME PERMITS.

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SO WITH THAT, I WILL INTRODUCE

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OUR ESTEEMED SPEAKERS TODAY. WE

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HAVE DR. MAXWELL LAWS, A

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NEUROSURGERY RESIDENT AND

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POST-DOC IN THE FUNCTIONAL

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NEUROSURGERY SECTION OF NINDS.

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WE ALSO HAVE DR. NADIA BIASSOU,

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WHO IS SENIOR CLINICIAN IN THE

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RADIOLOGY IMAGING SCIENCES HERE

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AT THE CLINICAL CENTER. WE HAVE

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DR. PJ CIMINO, HEAD OF THE

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NEUROPATHOLOGY UNIT SURGICAL

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NEUROLOGY BRANCH OF NINDS AND

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DR. DESMOND BROWN, ACI AND HEAD

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OF NEUROSURGICAL ONCOLOGY UNIT

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IN THE SURGICAL NEUROLOGY BRANCH

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NINDS. THEY WILL PRESENT A CASE

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OF ANNA PLASTIC AND ASTRO

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CYTOMA. WITH THAT I WILL HAND IT

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TO DR. LAWS.  ANAPLASTIC

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>> THANK YOU VERY MUCH,

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EVERYBODY. SO WE HAVE NO

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DISCLDISCLOSURES. OUR PATIENT

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INITIALLY PRESENTED TO OUR

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SERVICE IN SEPTEMBER OF 20 --

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2011, HE WAS A 30-YEAR-OLD AT

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THE TIME, THIS WAS FALL

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FOLLOWING A PARTIAL RESECTION OF

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A WHO GRADE 3 ANAPLASTIC ASTRO

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CYTOMA PERFORMED AT GEORGETOWN

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HOSPITAL. HE HAD RECEIVE HAD

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STANDARD OF CARE RADIATION

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THERAPY AND CURRENT

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TILAZOLAMIDE. HE INITIALLY

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INVOLVED FIELD RADIATION AND

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FOLLOWING THAT HAD TEN CYCLES OF

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TEMZOLAMIDE STOPPED IN SEPTEMBER

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OF 2012 DUE TO FATIGUE AND LOW

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NEUTROPHIL COUNT. THE PATIENT

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UNDERWENT LATER PATHOLOGIC

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TESTING THROUGH THE NIH AND IT

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SHOWED HE HAD A TP 53 MUTATION

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AND IDH MUTATION AS WELL AS CDK

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4 COPY NUMBER GAIN. THE PATIENT

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WAS FOLLOWED BY THE NIH

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NEUROONCOLOGY BRANCH FOR THE

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NEXT TEN YEARS. AND HE HAD

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STABLE SCANS AND HE WAS DOING

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WELL CLINICALLY. HE HAD AN

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INTERVAL SCAN PERFORMED IN MAY

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OF 2023 WHICH SHOWED A NEW

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11-MILLIMETER ENHANCING NO DUAL

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WITHIN THE PREVIOUS RESECTION

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BED WHICH WAS CONCERNING FOR

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RECURRENCE OF HIS DISEASE.  IN

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JUNE OF THAT YEAR, THE PATIENT

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UNDERWENT A REDO RIGHT FAN TOLL

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CRANEIOTMY FOR RESECTION OF

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TUMOR WITH DR. BROWN.  THIS

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PATHOLOGY WAS CONSISTENT WITH

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HIGH GRADE GLIOMA AND PATIENT

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WAS SEEN IN FOLLOW-UP CLINIC A

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MONTH LATER WITH A REPEAT MRI. 

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AT THAT TIME, WE FELT THAT IT

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WAS APPROPRIATE TO MANAGE

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CONSERVATIVELY WITH GETTING

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REPEAT IMAGING IN OCTOBER AND

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THEN CONSIDERING RESTARTING THE

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PATIENT ON TEMOZOLOMIDE IN

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OCTOBER. SO WE HAD OBTAINED THAT

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SCAN AND IT SHOWED A LARGE

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ENHANCING MASS WITHIN THE PRIOR

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RESECTION CAVITY. SO THE PATIENT

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UNDERWENT SURGERY AGAIN. ON

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OCTOBER 12TH. AND THE PATIENT

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HAD A HOSPITALIZATION SOMEWHERE

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AROUND 12 DAYS AND WAS

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DISCHARGED TO REHAB. SO THE

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PATIENT THEN CONTACTED OUR

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CLINIC AND OR THE PATIENT

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HEALTHCARE PROVIDERS CONTACTED

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OUR CLINIC AND INFORMED THE

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PATIENT DEVELOPED NEW SOME LENS

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AND VOMITING. SO THE PATIENT WAS

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TRANSFERRED TO THE WASHINGTON

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HOSPITAL CENTER AT THE

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WASHINGTON HOSPITAL CENTER THE

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PATIENT WAS NOTED TO HAVE

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HYDROCEPHALUS, CONCERNING FOR

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EITHER TUMOR ASSOCIATED

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HYDROCEPHALUS AND SO WE

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TRANSFERRED THE PATIENT BACK TO

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THE NIH FOR CONSIDERATION OF A

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CENTRIC LAR PERITONEAL SHUNT. SO

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WE PLACED A SHUNT ON NOVEMBER 20

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WITHOUT ANY ISSUE AND THE

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PATIENT WAS ADMITTED TO ICU.

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THIS PATIENT HAD PERSISTENT

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GNASHIA AND NEUROLOGIC DECLINE.

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WE OBTAINED INTERVAL IMAGING

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GROWING A GROWING SUB DO YOU

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RECALL FLUID CONNECTION FOR

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TUMOR ASSOCIATED CYST. THE

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PATIENT DISTIER YOUR RATED

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NEUROLOGICALLY SO WE PERFORM --

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DETERIORATED NEUROLOGICALLY SO

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WE PERFORMED HOLE ASPIRATION AND

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AND CSF TO DIALED THE SHUNT FROM

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5 TO 7 TO SLOW THE CSF. THE

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PATIENT CONTINUED WITH

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NEUROLOGIC DECLINE AND SO WE

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PLACE ADN'T RIGHT FRONTAL EVD TO

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ADDRESS PATIENT ALTERED MENTAL

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STATUS AND HYDROCEPHALUS. THE

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CFS FROM THE ASPIRATION GREW

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CANDIDA PARAPSILOSIS SO WE WERE

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CONCERNED THE PATIENT HAS FUNGAL

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MENINGITIS AND STARTED ON FLEW

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CON SOLVE. WE HAD SAMPLES FROM

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THE EVD, THOSE CONTINUED TO GROW

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CANDIDA AND FUNGAL CULTURES.  SO

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WE ALSO CONCERNED THE TUMOR

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RECURRED AND CONFOUNDD BY THIS

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FUNGAL INFECTION AND WE DID

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PERFORM EXTERNAL BEAM READIATION

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IN EARLY DECEMBER TO TRY TO GET

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TUMOR CONTROL. THE PATIENT

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CONTINUED TO HAVE CHALLENGES

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WITH THIS INFECTION SO WE

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EXPLANTED THE SHUNT AND REPLACED

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THE EVD TO TRY TO EXCHANGING THE

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HARDWARE AND PLACED A RIGHT SUB

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DO YOU RECALL DRAIN TO TRY TO

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DRAIN THE TUMOR ASSOCIATED CYST.

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CSF CONTINUED TO BE -- HAVE

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EVIDENCE OF INFECTION. AND THEN

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WE -- THE PARENTED WAS HAVING

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FURTHER ISSUES WITH THESE THE

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SHUNT AND THE EVD, BASICALLY WE

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HAD TO CONTINUOUSLY TRY TO

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EXCHANGING THE FLUID AND FLUSH

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THE DRAINS. THE PATIENT BECAME

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MORE PROGRESSIVELY SOME LENT AND

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WE CHANGED CODE STATUS TO DNR

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DNI. EVENTUALLY TRANSITIONED THE

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PATIENT TO HOSPICE CARE DECEMBER

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14 AND HE EXPIRED DECEMBER 29. I

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WILL TRANSITION TO DR. BIASSOU

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TO TALK ABOUT THE RADIOLOGY FOR

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THE PATIENT.

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>> THANK YOU. AS
MENTIONED, THE

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PATIENT ORIGINALLY WAS TREATED

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AT GEORGETOWN UNIVERSITY

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HOSPITAL SO THE INITIAL SET OF

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IMAGING HERE IS FROM GEORGETOWN.

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AND I JUST WANTED TO POINT TO

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YOU THE APPEARANCE OF THE MASS

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PRIOR TO THEIR SURGICAL

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RESECTION. SO THIS WAS -- IF YOU

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LOOK ON THE FIRST IMAGE ON THE

191
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LEFT THIS IS A NON-CONTRAST T 1

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POST CONTRAST T 2. THERE IS A

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FLAIR WEIGHTED SEQUENCE HERE.

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AND DWI WHICH BASICALLY ONE USES

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TO TRY TO UNDERSTAND WHETHER

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THERE'S DIFFUSION RESTRICTION.

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WHAT WE SEE HERE IS A

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NON-ENHANCING OR FAINTLY

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00:08:15,463 --> 00:08:19,100
ENHANCING MASS THAT HAS PERT

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00:08:19,100 --> 00:08:23,070
NACHOS MATERIAL THAT DOES

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00:08:23,070 --> 00:08:25,740
RESTRICT. THE PATIENT UNDERWENT

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00:08:25,740 --> 00:08:27,675
SURGICAL RESECTION.  THIS IS THE

203
00:08:27,675 --> 00:08:31,879
PRE-CONTRAST T 1 POST CONTRAST T

204
00:08:31,879 --> 00:08:33,514
1 P PRE-OPERATIVE, THIS IS THEIR

205
00:08:33,514 --> 00:08:35,616
POST SURGICAL T 1 POST CONTRAST

206
00:08:35,616 --> 00:08:37,451
IMAGE. WHAT WE SEE IS A SURGICAL

207
00:08:37,451 --> 00:08:40,988
BED HERE. AND WE SEE A LITTLE

208
00:08:40,988 --> 00:08:42,256
ENHANCEMENT SO THE QUESTION

209
00:08:42,256 --> 00:08:44,625
ARISES IS TO WHETHER YOU GOT

210
00:08:44,625 --> 00:08:46,527
EVERYTHING OR IF THERE'S SOME

211
00:08:46,527 --> 00:08:49,296
RESIDUAL TUMOR THAT'S LEFT.  AND

212
00:08:49,296 --> 00:08:51,298
WAY WHICH WE CAN ANSWER THAT

213
00:08:51,298 --> 00:08:54,635
QUESTION IS TO LOOK AT THE

214
00:08:54,635 --> 00:08:57,204
PRE-CONTRAST T 1 POST-OPERATIVE

215
00:08:57,204 --> 00:09:00,341
STUDY. SO HERE THERE IS NO

216
00:09:00,341 --> 00:09:03,944
CONTRAST. WE DO SEE WHAT LOOKS

217
00:09:03,944 --> 00:09:06,280
LIKE HYPERSIGNAL. THIS IS

218
00:09:06,280 --> 00:09:08,048
CONSISTENT WITH HEMORRHAGE

219
00:09:08,048 --> 00:09:09,583
NON-ENHANCEMENT AND THIS IS

220
00:09:09,583 --> 00:09:11,819
CONFIRMED ON THE SUSCEPTIBILITY

221
00:09:11,819 --> 00:09:18,893
WEIGHTED IMAGE SEEN BELOW.  AS

222
00:09:18,893 --> 00:09:19,927
DR. LAWS MENTIONED THE PATIENT

223
00:09:19,927 --> 00:09:21,896
WAS FOLLOWED WITH MULTIPLE

224
00:09:21,896 --> 00:09:25,900
SUBSEQUENT MRI STUDIES,

225
00:09:25,900 --> 00:09:28,869
BASICALLY FOUND TO BE DOING

226
00:09:28,869 --> 00:09:31,739
QUITE WELL AND NO RECURRENCE

227
00:09:31,739 --> 00:09:34,375
UNTIL 2023 ON ROUTINE FOLLOW-UP

228
00:09:34,375 --> 00:09:36,143
SCAN THERE WAS A ENHANCING NO

229
00:09:36,143 --> 00:09:37,912
DUAL HERE WE SEE THE RESIDUAL

230
00:09:37,912 --> 00:09:39,246
SURGICAL CAVITY AND EVIDENCE OF

231
00:09:39,246 --> 00:09:40,915
PRIOR SURGERY BUT WE DO SEE

232
00:09:40,915 --> 00:09:44,018
ENHANCING NO DUAL HERE.  SO THE

233
00:09:44,018 --> 00:09:46,987
QUESTION IS WHAT IS THAT, IS

234
00:09:46,987 --> 00:09:47,955
THAT RECURRENCE? IT LOOKS LIKE

235
00:09:47,955 --> 00:09:52,560
IT IS.  WE CONFIRMED THAT WITH A

236
00:09:52,560 --> 00:09:56,630
PERFUSION SCAN. THIS IS

237
00:09:56,630 --> 00:09:58,732
PERFUSION SCANS ARE DONE

238
00:09:58,732 --> 00:10:00,301
DIFFERENTLY, WE LEAK AT THE

239
00:10:00,301 --> 00:10:02,937
CURVE OF UPTAKE OF ENHANCEMENT.

240
00:10:02,937 --> 00:10:06,574
HERE WE DO T AS A MAP AND THIS

241
00:10:06,574 --> 00:10:09,243
IS A MAP OF THE PRE-CONTRAST OF

242
00:10:09,243 --> 00:10:11,579
THE POST CONTRAST PERFUSION

243
00:10:11,579 --> 00:10:13,347
MINUS PRE-CONTRAST PERFUSION

244
00:10:13,347 --> 00:10:16,650
SCAN. SO IT REALLY SHOWS YOU

245
00:10:16,650 --> 00:10:20,020
VERY CLEARLY THE HYPERPERFUSION

246
00:10:20,020 --> 00:10:21,655
OF THIS ENHANCING NO DUAL. ONE

247
00:10:21,655 --> 00:10:26,594
OF THE THINGS YOU MAY READ ABOUT

248
00:10:26,594 --> 00:10:30,197
IN THE A LITERATURE IS

249
00:10:30,197 --> 00:10:33,634
HYPERSENSE TVTY IS CONFUSED WITH

250
00:10:33,634 --> 00:10:35,936
RESTRICTION, THAT'S WHAT WE

251
00:10:35,936 --> 00:10:38,005
EXPECTED TO SEE ON THE WHI

252
00:10:38,005 --> 00:10:39,406
SEQUENCE WHERE THE HIGHLIGHTER

253
00:10:39,406 --> 00:10:41,542
IS POINT BUD WE DON'T SEE THAT.

254
00:10:41,542 --> 00:10:43,377
THIS IS SOMETHING I MENTIONED TO

255
00:10:43,377 --> 00:10:45,613
FOLLOWS WHEN THEY ARE ROTATING

256
00:10:45,613 --> 00:10:47,948
THROUGH GEORGETOWN AND GW THAT

257
00:10:47,948 --> 00:10:50,584
WITH CERTAIN TUMORS YOU DON'T

258
00:10:50,584 --> 00:10:51,252
ALWAYS SEE DIFFUSION

259
00:10:51,252 --> 00:10:53,554
RESTRICTION. YOU SEE WITH SOME

260
00:10:53,554 --> 00:10:55,623
TUMORS, LYMPHOMA, TIGHTLY PACKED

261
00:10:55,623 --> 00:10:58,592
CELLS, THOSE USUALLY PRESENT

262
00:10:58,592 --> 00:11:00,027
WITH DIFFUSION RESTRICTION BUT

263
00:11:00,027 --> 00:11:02,162
NOT NECESSARILY GLIOMA. SO IF

264
00:11:02,162 --> 00:11:03,998
YOU DON'T SEE DIFFUSION

265
00:11:03,998 --> 00:11:06,400
RESTRICTED FOCUS ASSOCIATED WITH

266
00:11:06,400 --> 00:11:08,369
A NODULE PLEASE DON'T THINK YOU

267
00:11:08,369 --> 00:11:10,137
CAN THROW THAT AWAY, IT IS

268
00:11:10,137 --> 00:11:10,938
SOMETHING THAT NEEDS TO BE

269
00:11:10,938 --> 00:11:12,740
FOLLOWED UP. THE SECOND THING

270
00:11:12,740 --> 00:11:19,113
THAT WE HAVE TO ALSO THINK ABOUT

271
00:11:19,113 --> 00:11:22,216
IF YOU DON'T SEE ENHANCEMENT

272
00:11:22,216 --> 00:11:24,385
ELEVATED PERFUSION WHICH WE

273
00:11:24,385 --> 00:11:26,554
DON'T BUT IF WE DO YOU HAVE TO

274
00:11:26,554 --> 00:11:27,988
SEE IF THAT'S SOMETHING THAT

275
00:11:27,988 --> 00:11:29,523
MIGHT BE ASKING THE ELEVATED

276
00:11:29,523 --> 00:11:30,991
PERFUSION. SO THAT'S WHY WE LOOK

277
00:11:30,991 --> 00:11:34,662
AT THE SWI WITH SUSCEPTIBILITY

278
00:11:34,662 --> 00:11:37,298
IMAGE SO SEE IF THERE IS

279
00:11:37,298 --> 00:11:38,365
HEMORRHAGE ASSOCIATED THAT MIGHT

280
00:11:38,365 --> 00:11:39,800
BE MASKING YOUR ABILITY TO SEE

281
00:11:39,800 --> 00:11:42,903
THE ELEVATED PERFUSION. SO WE

282
00:11:42,903 --> 00:11:47,441
DON'T SEE THAT, IF YOU SEE

283
00:11:47,441 --> 00:11:50,210
ELEVATED PERFUSION YOU DON'T SEE

284
00:11:50,210 --> 00:11:52,813
A REASON, THIS IS A HIGHLY PER

285
00:11:52,813 --> 00:11:55,749
FUSED LESION LIKELY HIGH GRADE

286
00:11:55,749 --> 00:11:59,053
GLIOMA. IF YOU LOOK CLOSE, I

287
00:11:59,053 --> 00:12:00,220
DON'T KNOW FOR THOSE OF YOU IN

288
00:12:00,220 --> 00:12:01,522
THE AUDIENCE IF YOU LOOK CLOSE

289
00:12:01,522 --> 00:12:03,357
YOU CAN SEE THAT THIS PATIENT

290
00:12:03,357 --> 00:12:05,259
HAS HAD PRIOR RADIATION THERAPY

291
00:12:05,259 --> 00:12:15,803
BECAUSE WE DO SEE POST RADIATION

292
00:12:17,738 --> 00:12:19,306
ANGIOPATHY, SO HEMORRHAGE WITH

293
00:12:19,306 --> 00:12:20,641
THE BRAIN PARENCHYMA AND

294
00:12:20,641 --> 00:12:22,977
COINCIDES WITH THE HISTORY OF

295
00:12:22,977 --> 00:12:25,479
BRAIN RADIATION THERAPY.  AS DR.

296
00:12:25,479 --> 00:12:27,815
LAWS SAID THIS LESION WAS

297
00:12:27,815 --> 00:12:29,950
RESECTED ON FOLLOW-UP SCANS IN

298
00:12:29,950 --> 00:12:32,519
OCTOBER OF 2023. THERE IS

299
00:12:32,519 --> 00:12:33,988
ANOTHER MASS THAT'S MUCH BIGGER,

300
00:12:33,988 --> 00:12:37,524
THERE IS A LARGE AMOUNT OF

301
00:12:37,524 --> 00:12:39,059
SURROUNDING EDEMA ASSOCIATED

302
00:12:39,059 --> 00:12:41,161
WITH THAT. IF OWE LOOK AT THE

303
00:12:41,161 --> 00:12:43,731
PERFUSION SCAN WE SEE IT IS

304
00:12:43,731 --> 00:12:46,400
HIGHLY PER FUSED SO A HIGH --

305
00:12:46,400 --> 00:12:49,837
PERFUSED SO A HIGH GRADE GLIOMA

306
00:12:49,837 --> 00:12:51,305
UNTIL PROVEN OTHERWISE BY

307
00:12:51,305 --> 00:12:52,940
RADIATION CRITERIA. THE PATIENT

308
00:12:52,940 --> 00:13:00,914
UNDERWENT SURGICAL RESECTION YES

309
00:13:00,914 --> 00:13:03,751
WANT TO MAKE SURE WE HAVE GOTTEN

310
00:13:03,751 --> 00:13:05,619
ALL THE TUMOR, THE POST CONTRAST

311
00:13:05,619 --> 00:13:07,421
T # SHOWS ENHANCEMENT ALONG THE

312
00:13:07,421 --> 00:13:09,089
PERIPHERY OF THE SURGICAL CAVITY

313
00:13:09,089 --> 00:13:10,357
AND YOU ALWAYS CONCERN THAT

314
00:13:10,357 --> 00:13:11,925
MAYBE THERE IS A LITTLE BIT OF

315
00:13:11,925 --> 00:13:15,596
RESIDUAL TUMOR THERE. WE LOOK AT

316
00:13:15,596 --> 00:13:17,297
PRE-CONTRAST STUDY AND SEE THAT

317
00:13:17,297 --> 00:13:22,102
IS REALLY ASSOCIATED WITH

318
00:13:22,102 --> 00:13:23,537
POST-OPERATIVE HEMORRHAGE WHICH

319
00:13:23,537 --> 00:13:25,072
IS CONFIRMED ON THE SWI

320
00:13:25,072 --> 00:13:28,142
SEQUENCE. THE IMMEDIATE POSTOP

321
00:13:28,142 --> 00:13:32,279
HEAD CT THAT WAS DONE SHOWS POST

322
00:13:32,279 --> 00:13:34,248
SURGICAL CHANGES, RESIDUAL

323
00:13:34,248 --> 00:13:35,616
HEMORRHAGE BUT I WANT TO POINT

324
00:13:35,616 --> 00:13:40,554
TO YOU IMMEDIATELY POSTOP WE

325
00:13:40,554 --> 00:13:42,923
DON'T HAVE EVIDENCE OF

326
00:13:42,923 --> 00:13:44,291
HYDROCEPHALUS. THE LATERAL

327
00:13:44,291 --> 00:13:45,392
VENTRICLES ARE NORMAL SIZE.

328
00:13:45,392 --> 00:13:50,064
THERE IS A LITTLE POST-OPERATIVE

329
00:13:50,064 --> 00:13:52,800
PNEUMOSYPHILOUS. BUT ONE MONTH

330
00:13:52,800 --> 00:13:56,036
LATER THE PATIENT COMES BACK

331
00:13:56,036 --> 00:14:00,207
NON-CONTRAST HEAD CT IS

332
00:14:00,207 --> 00:14:01,909
PERFORMED.  THERE'S LARGE AMOUNT

333
00:14:01,909 --> 00:14:03,243
OF HYDROCEPHALUS, THIS IS THE

334
00:14:03,243 --> 00:14:06,914
SURGICAL CAVITY AND WE SEE A

335
00:14:06,914 --> 00:14:12,619
SMALL SUB DURAL FLUID

336
00:14:12,619 --> 00:14:14,955
COLLECTING. THE PATIENT HAD VP

337
00:14:14,955 --> 00:14:19,693
SHUNT PLACED IN THE VENTRICULAR

338
00:14:19,693 --> 00:14:25,065
SYSTEM. YOU STILL SEE THE

339
00:14:25,065 --> 00:14:26,567
SUBDURAL FLUID COLLECTION, THERE

340
00:14:26,567 --> 00:14:29,036
IS A SECOND VP SHUNT PUT IN

341
00:14:29,036 --> 00:14:31,105
PLACE TO TRY TO REDUCE THAT AND

342
00:14:31,105 --> 00:14:34,875
THERE IS A SMALL RESIDUAL

343
00:14:34,875 --> 00:14:36,443
IMPROVEMENT, I WANTED TO SHOW

344
00:14:36,443 --> 00:14:40,180
THERE IS LIKELY EPIDURAL AND

345
00:14:40,180 --> 00:14:43,450
SUBDURAL FLUID COLLECTION AND

346
00:14:43,450 --> 00:14:48,555
THE LEFT TEMPORAL HORN APPEARED

347
00:14:48,555 --> 00:14:51,558
ENTRAPPED. AFTER MULTIPLE SCANS

348
00:14:51,558 --> 00:14:53,761
THAT HAPPENED BETWEEN THE LAST

349
00:14:53,761 --> 00:14:55,662
SCAN I SHOWED AND THE ONE HERE,

350
00:14:55,662 --> 00:14:57,898
ON THE LEFT WHERE ALL THE DRAINS

351
00:14:57,898 --> 00:15:00,334
HAVE NOW BEEN ALL THE VP SHUNTS

352
00:15:00,334 --> 00:15:01,568
HAVE BEEN REMOVED PROBABLY

353
00:15:01,568 --> 00:15:04,204
BECAUSE THERE'S BEEN EVIDENCE

354
00:15:04,204 --> 00:15:05,873
FROM CSF THERE IS INFECTION.

355
00:15:05,873 --> 00:15:08,642
THEY REMOVED ALL OF THAT. WE CAN

356
00:15:08,642 --> 00:15:10,644
SEE THE SUBDURAL FLUID

357
00:15:10,644 --> 00:15:12,012
COLLECTION INCREASED THE

358
00:15:12,012 --> 00:15:15,015
VENTRICULAR SIZE ENLARGED

359
00:15:15,015 --> 00:15:19,119
DESPITE MANY WEEKS OF HAVING THE

360
00:15:19,119 --> 00:15:21,188
VP SHUNT IN PLACE TO HELP DRAIN

361
00:15:21,188 --> 00:15:26,593
THAT. THEY THEN PUT IN A RIGHT

362
00:15:26,593 --> 00:15:28,929
FRONTAL SURGICAL DRAIN AND WE DO

363
00:15:28,929 --> 00:15:32,132
SEE AN IMPROVEMENT OF THE

364
00:15:32,132 --> 00:15:34,101
EPIDURAL AND SUBDURAL FLUID

365
00:15:34,101 --> 00:15:38,071
COLLECTION AS WELL AS SOME

366
00:15:38,071 --> 00:15:40,440
IMPROVEMENT IN THE SIZE OF THE

367
00:15:40,440 --> 00:15:42,843
VENTRICLE, IT STILL REMAINS

368
00:15:42,843 --> 00:15:44,845
ENLARGED BUT AFTER ABOUT A FEW

369
00:15:44,845 --> 00:15:47,214
WEEKS, THIS IS ON DECEMBER 14,

370
00:15:47,214 --> 00:15:49,983
YOU CAN SEE THAT THOSE FLUID

371
00:15:49,983 --> 00:15:51,185
COLLECTIONS ARE STARTING TO

372
00:15:51,185 --> 00:15:56,423
REACCUMULATE.  THEN THE PATIENT

373
00:15:56,423 --> 00:16:01,695
IS SENT TO HOSPICE. I WANT TO

374
00:16:01,695 --> 00:16:03,630
INTRODUCE DR. CIMINO WHO WILL

375
00:16:03,630 --> 00:16:08,068
TALK ABOUT PATHOLOGY.

376
00:16:08,068 --> 00:16:10,771
>> THANK YOU. SO I'M GOING
TO GO

377
00:16:10,771 --> 00:16:13,540
OVER THIS PATIENT'S PATHOLOGY IN

378
00:16:13,540 --> 00:16:15,442
A TIME LINE FORMAT BECAUSE IT

379
00:16:15,442 --> 00:16:17,311
GETS COMPLICATED AS WE GO OVER

380
00:16:17,311 --> 00:16:20,080
TIME SO I WANT TO START WITH THE

381
00:16:20,080 --> 00:16:21,481
INITIAL EXCISION THAT HAPPENED

382
00:16:21,481 --> 00:16:24,251
IN GEORGETOWN IN 2011.

383
00:16:24,251 --> 00:16:25,786
UNFORTUNATELY DON'T HAVE ANY

384
00:16:25,786 --> 00:16:27,221
PATHOLOGY SLIDES TO REVIEW SO

385
00:16:27,221 --> 00:16:29,323
I'M GOING TO DISCUSS THE

386
00:16:29,323 --> 00:16:31,458
PATHOLOGY WHAT WE ARE SEEING. ON

387
00:16:31,458 --> 00:16:34,127
THE ACTUAL HISTOPATHOLOGY WE SAW

388
00:16:34,127 --> 00:16:37,231
DIFFUSE ASTROSITIC GLIOMA,

389
00:16:37,231 --> 00:16:40,968
ELEVATED MITOTIC ACTIVITY AND NO

390
00:16:40,968 --> 00:16:42,169
MICROVASCULAR PROLIFERATION OR

391
00:16:42,169 --> 00:16:44,504
NECROSIS. I WILL COME BACK HOW

392
00:16:44,504 --> 00:16:45,939
WE GRADE THE TUMORS AND WHY THE

393
00:16:45,939 --> 00:16:49,610
FEATURES ARE IMPORTANT.  ON

394
00:16:49,610 --> 00:16:51,245
IMMUNOHISTOCHEMISTRY IT HAD A

395
00:16:51,245 --> 00:16:54,381
GLIAL PHENOTYPE SO POSITIVE FOR

396
00:16:54,381 --> 00:16:58,085
GLIAL ASITIC PROTEIN OR GFAPP.

397
00:16:58,085 --> 00:17:01,955
POSITIVE FOR R 312H MUTATION ONE

398
00:17:01,955 --> 00:17:04,057
OF THE MAIN FEATURES NOW THAT WE

399
00:17:04,057 --> 00:17:07,261
USE TO CATEGORIZE DIFFUSE

400
00:17:07,261 --> 00:17:09,263
GLIOMAS IS THE PRESENCE OF IDH

401
00:17:09,263 --> 00:17:15,802
MUTATION.  ATRP WAS RETAINED P53

402
00:17:15,802 --> 00:17:18,572
PROLIFERATED AND ELEVATED 8%

403
00:17:18,572 --> 00:17:20,340
INDICATING MORE PROLIFERATIVE

404
00:17:20,340 --> 00:17:24,211
THAN LOWER GRADE TUMOR. THEN

405
00:17:24,211 --> 00:17:28,715
WHEN WE THINK ABOUT IDH MUTANT

406
00:17:28,715 --> 00:17:32,819
DIFFUSE GLIOMAS, IT CAN BE

407
00:17:32,819 --> 00:17:35,322
PRESENT IN AL GO DEN DROVE

408
00:17:35,322 --> 00:17:37,124
GLIOMA AND HOW WE DISTINGUISH IS

409
00:17:37,124 --> 00:17:42,095
ROOKING FOR PA P 19 Q CODE

410
00:17:42,095 --> 00:17:44,264
DELETION BACK IN TIME IN SITU

411
00:17:44,264 --> 00:17:45,465
HYBRIDIZATION WAS PERFORMED AND

412
00:17:45,465 --> 00:17:49,703
IT WAS NEGATIVE FOR Q CODE

413
00:17:49,703 --> 00:17:53,307
DELETION. THAT'S WNS WHO GRADE

414
00:17:53,307 --> 00:17:57,844
3, THE FORMER TERM WAS ANN

415
00:17:57,844 --> 00:18:00,881
PLASTIC CYTOMAPPED A LITTLE HOW

416
00:18:00,881 --> 00:18:03,450
WE GRADE, IN 2008 THE IDH

417
00:18:03,450 --> 00:18:05,018
MUTATION WAS INTRODUCED AS

418
00:18:05,018 --> 00:18:07,521
CRITERIA FOR GRADING BUT

419
00:18:07,521 --> 00:18:08,422
OFFICIALLY 2016 THERE WAS ADDED

420
00:18:08,422 --> 00:18:12,392
TO THE WHO CRITERIA. SO IT WAS

421
00:18:12,392 --> 00:18:15,829
THAT IF DIFFUSE ASTRO SIGH

422
00:18:15,829 --> 00:18:16,897
MOMMA, NO OTHER FEATURES GRADE

423
00:18:16,897 --> 00:18:19,599
2. WITH INCREASED MITOTIC

424
00:18:19,599 --> 00:18:22,636
ACTIVITY THEN BUMPS UP TO GRADE

425
00:18:22,636 --> 00:18:25,772
3 ANN PLASTIC ASTRO CYTOMA

426
00:18:25,772 --> 00:18:28,275
MUTANT, IF IT HAD NECROSIS

427
00:18:28,275 --> 00:18:30,911
NEITHER WHICH THE PATIENT HAD IT

428
00:18:30,911 --> 00:18:33,947
MOVES TO THE GLIAL BLASTOMA IDH

429
00:18:33,947 --> 00:18:36,249
MUTANT. THIS IS NO LONGER

430
00:18:36,249 --> 00:18:38,585
ACCEPTED NOMENCLATURE, IN

431
00:18:38,585 --> 00:18:41,989
SEPTEMBER 2021 IT WAS CHANGED SO

432
00:18:41,989 --> 00:18:43,123
GLIOBLASTOMA IS ASSOCIATE WITH

433
00:18:43,123 --> 00:18:44,257
THE WILD TYPE TUMORS SO NOW WE

434
00:18:44,257 --> 00:18:46,626
HAVE A COUPLE OF WAYS TO GRADE.

435
00:18:46,626 --> 00:18:48,595
HISTOLOGICAL OR MOLECULAR

436
00:18:48,595 --> 00:18:51,965
CRITERIA. SO AGAIN ASTRO CYTOMA,

437
00:18:51,965 --> 00:18:54,835
IDH MUTANT WHO GRADE 2 IF NO

438
00:18:54,835 --> 00:18:57,237
FEATURES IF ELEVATED MITOTIC

439
00:18:57,237 --> 00:19:00,007
ACTIVITY, YOU GET TO GRADE 3.

440
00:19:00,007 --> 00:19:02,476
THEN EITHER MICROVASCULAR

441
00:19:02,476 --> 00:19:04,244
PROLIFERATION OR NECROSIS ON

442
00:19:04,244 --> 00:19:08,148
HISTOLOGY OR CDK AND HOMOZYGOUS

443
00:19:08,148 --> 00:19:10,884
DELETION BASED UPON MOLECULAR

444
00:19:10,884 --> 00:19:16,056
FINDINGS ELEVATE TO WHO GRADE 4 

445
00:19:16,056 --> 00:19:17,391
AND BECAUSE I WANT TO BRING THIS

446
00:19:17,391 --> 00:19:20,727
UP BECAUSE THERE IS THE TIME

447
00:19:20,727 --> 00:19:22,262
SPAN OF WHEN THIS WAS DIAGNOSED

448
00:19:22,262 --> 00:19:24,598
AND RELEVANT NOMENCLATURE

449
00:19:24,598 --> 00:19:25,298
CHANGES EVERYTHING I WANT TO

450
00:19:25,298 --> 00:19:27,300
TALK MORE ABOUT THE RELEVANT

451
00:19:27,300 --> 00:19:30,070
CHANGES IN THE 2021 CNS. SO HERE

452
00:19:30,070 --> 00:19:33,173
I SHOW YOU THE COVERS FOR THE

453
00:19:33,173 --> 00:19:35,475
WHO OVER TIME AND REALLY WAS

454
00:19:35,475 --> 00:19:37,277
MORE HISTOLOGY AND IMMUNOCHEST

455
00:19:37,277 --> 00:19:39,479
CHEMISTRY BASED UNTIL RECENTLY

456
00:19:39,479 --> 00:19:41,281
WHEN WHEN WE STARTED USING

457
00:19:41,281 --> 00:19:42,749
GENETICS AND EPIGENETIC

458
00:19:42,749 --> 00:19:43,617
SIGNATURES WHICH I WILL TALK

459
00:19:43,617 --> 00:19:45,052
ABOUT IN ORDER TO CLASSIFY THE

460
00:19:45,052 --> 00:19:48,488
TUMORS.  SO THEY MOVE FROM

461
00:19:48,488 --> 00:19:50,957
RATHER THAN ROMAN NUMERALS FOR

462
00:19:50,957 --> 00:19:54,795
GRADING. THEY TURNED TO IN CLASS

463
00:19:54,795 --> 00:19:57,130
GRADING.  SO INSTEAD OF DIFFUSE

464
00:19:57,130 --> 00:20:01,501
ASTRO CYTOMA TO ANN PLASTIC SAY

465
00:20:01,501 --> 00:20:02,969
TOE MA TO GLIAL BLASTOMA, IT IS

466
00:20:02,969 --> 00:20:06,406
ASTRO CYTOMA GRADES 2, 3 AND 4

467
00:20:06,406 --> 00:20:08,875
SO ANN PLASTIC IS REMOVED.  WE

468
00:20:08,875 --> 00:20:10,710
HAVE COMBINED HISTOLOGIC AND

469
00:20:10,710 --> 00:20:11,545
MANY LOOK ALREADY GRADING FOR

470
00:20:11,545 --> 00:20:13,113
TUMORS AND THERE WAS FIRST DONE

471
00:20:13,113 --> 00:20:16,316
WITH IDH MUTANT TUMORS.  FOR

472
00:20:16,316 --> 00:20:19,352
WHAT WILL BE RELEVANT FOR THE

473
00:20:19,352 --> 00:20:20,787
PATIENT RESORNS, WE HAVE COME UP

474
00:20:20,787 --> 00:20:23,123
WITH THESE -- RECURRENCE WE HAVE

475
00:20:23,123 --> 00:20:26,326
COME UP WITH NOT HE WILL

476
00:20:26,326 --> 00:20:27,961
CLASSIFIED THE THE PATIENT TUMOR

477
00:20:27,961 --> 00:20:29,763
DOES NOT FIT INTO A NICE WHO

478
00:20:29,763 --> 00:20:32,933
CATEGORY. SO THE INITIAL TUMOR

479
00:20:32,933 --> 00:20:36,236
WE CAN CONSIDER IDH OR ASTRO

480
00:20:36,236 --> 00:20:39,706
CYTOMA IDH MUTANT WHO GRADE 3

481
00:20:39,706 --> 00:20:41,842
AND MAKES MORE SENSE IF WE THINK

482
00:20:41,842 --> 00:20:43,944
ABOUT THE LONG LIVE SURVIVAL FOR

483
00:20:43,944 --> 00:20:47,114
THIS IT IS THE IKH MUTATION

484
00:20:47,114 --> 00:20:48,448
DRIVING PROLONGED SURVIVAL

485
00:20:48,448 --> 00:20:52,319
RATHER THAN ANY TYPE OF GRADING 

486
00:20:52,319 --> 00:20:53,920
SO SECOND EXCISION PERFORMED

487
00:20:53,920 --> 00:21:00,360
HERE, BY DR. BROWN, WE SEE

488
00:21:00,360 --> 00:21:02,095
HEMOTOXIN HED STAIN SLIDE YOU

489
00:21:02,095 --> 00:21:03,697
HAVE TO LOOK AT ENOUGH TO TRUST

490
00:21:03,697 --> 00:21:05,565
ME THIS IS MINIMAL

491
00:21:05,565 --> 00:21:06,833
HYPERCELLULARITY AND WE SEE A

492
00:21:06,833 --> 00:21:09,069
LOT OF REACTIVE CHANGES RATHER

493
00:21:09,069 --> 00:21:11,605
THAN ACTIVE TUMOR SO I JUST

494
00:21:11,605 --> 00:21:14,241
HIGHLIGHTED HERE SOME HYPERPLAST

495
00:21:14,241 --> 00:21:16,276
TICK BLOOD VESSELS AS WELL AS

496
00:21:16,276 --> 00:21:19,813
RARE FRACTION SEEN AS

497
00:21:19,813 --> 00:21:21,915
VACCINATION IN THE BACK. WE SEE

498
00:21:21,915 --> 00:21:25,652
WHAT LOOKS LIKE REACTIVE ASTRO

499
00:21:25,652 --> 00:21:27,554
CYTOSIS AND NOT A LOT OF TUMOR

500
00:21:27,554 --> 00:21:30,190
CONTENT. WE DID NEXT GENERATION

501
00:21:30,190 --> 00:21:31,925
SEQUENCING AS PARTS OF STANDARD

502
00:21:31,925 --> 00:21:36,696
WORKUP, WE DID NOTE THAT THE IDH

503
00:21:36,696 --> 00:21:38,165
1 MUTATION WAS LOST SO WILD TYPE

504
00:21:38,165 --> 00:21:40,767
AND PROMOTER MUTATION AND TP 53

505
00:21:40,767 --> 00:21:42,402
MUTATIONS AT VERY LOW FREQUENCY

506
00:21:42,402 --> 00:21:45,505
SO HERE I'M SHOWING THE CHART,

507
00:21:45,505 --> 00:21:47,874
THE VF FREQUENCY IS LOW

508
00:21:47,874 --> 00:21:50,744
CONFIRMING THAT THE TUMOR BURDEN

509
00:21:50,744 --> 00:21:55,815
IS LOW IN THIS PATIENT. THEN FOR

510
00:21:55,815 --> 00:21:56,650
COMPLETENESS ONE OF THE THINGS

511
00:21:56,650 --> 00:21:58,985
WE DO HERE AT THE NIH AND

512
00:21:58,985 --> 00:22:01,188
BECOMING MORE PREVALENT IN

513
00:22:01,188 --> 00:22:03,023
SURGICAL NEUROPATHOLOGY IS

514
00:22:03,023 --> 00:22:05,058
LOOKING AT DNA METHYLATION BASED

515
00:22:05,058 --> 00:22:07,727
CLASSIFICATION SO HERE I'M

516
00:22:07,727 --> 00:22:11,164
SHOWING THE SEMINOLE PAPER BY

517
00:22:11,164 --> 00:22:12,699
CAPPER AND IDLEBURG GROUP THAT

518
00:22:12,699 --> 00:22:14,801
SHOWED WHAT YOU DO IS TAKE A

519
00:22:14,801 --> 00:22:18,138
RANDOM MACHINE LEARNING RANDOM

520
00:22:18,138 --> 00:22:21,074
CLASSIFIER, TAKE A WHOLE GENOME,

521
00:22:21,074 --> 00:22:22,709
WHOLE GENOME DNA METHYLATION

522
00:22:22,709 --> 00:22:25,378
ARRAY, FEED IT INTO THIS MACHINE

523
00:22:25,378 --> 00:22:26,713
LEARNING PROGRAM AND YOU CAN

524
00:22:26,713 --> 00:22:32,586
COME OUT WITH A CNS TUMOR BASED

525
00:22:32,586 --> 00:22:34,087
CLASSIFICATION. HERE IS ONE OF

526
00:22:34,087 --> 00:22:37,357
THE EXAMPLES THAT INCLUDES IDH

527
00:22:37,357 --> 00:22:38,725
TUMOR MEDULLAR BLASTOMA, ET

528
00:22:38,725 --> 00:22:43,096
CETERA, ET CETERA.  THEN IN OUR

529
00:22:43,096 --> 00:22:45,532
CLINICAL PRACTICE HOW WE

530
00:22:45,532 --> 00:22:47,434
INCORPORATE DNA METHYLATION IN

531
00:22:47,434 --> 00:22:49,703
SURGICAL NEUROPATHOLOGY, WE TAKE

532
00:22:49,703 --> 00:22:52,005
DNA FROM TISSUE BLOCKS, PREPARE

533
00:22:52,005 --> 00:22:55,342
THE DNA IN SUCH A WAY THAT IT IS

534
00:22:55,342 --> 00:22:56,243
HYBRIDIZES TO THE DNA

535
00:22:56,243 --> 00:22:58,812
METHYLATION ARRAYS AND IS READ

536
00:22:58,812 --> 00:23:01,281
BY EYE SCAN. THEN PUT THROUGH A

537
00:23:01,281 --> 00:23:01,982
BIOINFORMATIC PIPELINE AND WE

538
00:23:01,982 --> 00:23:05,685
COME OUT WITH, WE USE CURRENTLY

539
00:23:05,685 --> 00:23:08,121
A FEW DIFFERENT CLASSIFIERS, AND

540
00:23:08,121 --> 00:23:10,490
THEN WE ALSO PUTS IT ON THESE

541
00:23:10,490 --> 00:23:13,493
TWO DIMENSIONALITY REDUCTION

542
00:23:13,493 --> 00:23:16,863
MAPS, YOU CAN USE U MAP OR TISNY

543
00:23:16,863 --> 00:23:18,298
PLOTTING AND IT GIVES

544
00:23:18,298 --> 00:23:20,300
APPROXIMATION WHERE OTHER TUMORS

545
00:23:20,300 --> 00:23:21,501
WITH SIMILAR SIGNATURES MIGHT

546
00:23:21,501 --> 00:23:23,637
LAND. FROM THIS WE ALSO GET COPY

547
00:23:23,637 --> 00:23:24,904
NUMBER ALER RATIONS SO HERE I

548
00:23:24,904 --> 00:23:27,040
SHOW YOU A -- ALTERATIONS. SO

549
00:23:27,040 --> 00:23:28,508
HERE IS A COPY NUMBER PLOT ON

550
00:23:28,508 --> 00:23:32,078
THE X AXIS WE HAVE CHROMOSOMES

551
00:23:32,078 --> 00:23:33,613
LABELING FROM SMALL TO LARGEST

552
00:23:33,613 --> 00:23:36,249
SO CHROMOSOME 1 ON THE BOTTOM

553
00:23:36,249 --> 00:23:38,451
AND CHROMOSOME 22 OVER HERE. WE

554
00:23:38,451 --> 00:23:40,253
CAN GET SPECIFIC GENE

555
00:23:40,253 --> 00:23:42,756
METHYLATION FOR ESPECIALLY MGMT

556
00:23:42,756 --> 00:23:45,692
PROMOTER METHYLATION STATUS,

557
00:23:45,692 --> 00:23:46,393
NEUROONCOLOGIST USE FOR

558
00:23:46,393 --> 00:23:48,628
TREATMENT DECISIONS. THEN WE

559
00:23:48,628 --> 00:23:50,530
INTEGRATE THIS WITH THE CLINICAL

560
00:23:50,530 --> 00:23:52,432
RADIOGRAPHIC HISTOLOGICAL AND

561
00:23:52,432 --> 00:23:56,536
GENOMIC FINDI FINDINGS TO COME H

562
00:23:56,536 --> 00:24:00,674
INTEGRATED DIAGNOSIS. THIS

563
00:24:00,674 --> 00:24:01,908
SPECIMEN, METHYLATION CLASSIFIER

564
00:24:01,908 --> 00:24:03,276
CAME BACK WITH NO MATCH. WE HAVE

565
00:24:03,276 --> 00:24:05,312
THE U MAP DIMENSIONALITY

566
00:24:05,312 --> 00:24:07,180
CLUSTER, THE PATIENT'S TUMOR

567
00:24:07,180 --> 00:24:08,782
CLUSTERED WITHIN NORMAL OR

568
00:24:08,782 --> 00:24:09,883
REACTIVE BRAIN WHICH IS

569
00:24:09,883 --> 00:24:12,118
CONSISTENT WITH THE HISTOLOGICAL

570
00:24:12,118 --> 00:24:13,953
APPEARANCE AND WE HAVE A FLAT

571
00:24:13,953 --> 00:24:16,256
COPY NUMBER PLOT WHICH INDICATES

572
00:24:16,256 --> 00:24:19,626
VERY LOW TUMOR BURDEN. THE FINAL

573
00:24:19,626 --> 00:24:20,760
NEUROPATHOLOGICAL DIAGNOSIS FROM

574
00:24:20,760 --> 00:24:22,862
THE INTEGRATED WORK UP IS

575
00:24:22,862 --> 00:24:24,431
REACTIVE CHANGES WITH RESIDUAL

576
00:24:24,431 --> 00:24:30,003
OR NON-ACTIVE GLIOMA. SO THAT

577
00:24:30,003 --> 00:24:33,340
WAS THE GENE SPECIMEN AND THEN

578
00:24:33,340 --> 00:24:35,675
-- OCTOBER. DR. BROWN WENT BACK

579
00:24:35,675 --> 00:24:38,378
FOR ANOTHER EXCISION. AND HERE

580
00:24:38,378 --> 00:24:42,349
WE CAN SAY HNE STAINS AGAIN THIS

581
00:24:42,349 --> 00:24:44,117
IS HYPERCELLULAR OPPOSED TO THE

582
00:24:44,117 --> 00:24:47,120
LAST ONE WITH TUMOR NUCLEI. WE

583
00:24:47,120 --> 00:24:49,456
SEE ATYPICAL GLIAL CELLS, WE

584
00:24:49,456 --> 00:24:53,560
HAVE A LOT OF WHAT LOOKS LIKE

585
00:24:53,560 --> 00:24:56,529
MONSTROUS OR MULTI-NUCLEATED

586
00:24:56,529 --> 00:24:58,098
GIANT CELLS SO IT LOOKS VERY

587
00:24:58,098 --> 00:25:00,767
MUCH LIKE AGREE OWE MA AND HERE

588
00:25:00,767 --> 00:25:04,471
I CIRCLED A BUNCH -- GLIOMA, I

589
00:25:04,471 --> 00:25:07,741
CIRCLED MITOTIC, SO TO IS

590
00:25:07,741 --> 00:25:09,376
MITOTICALLY ACTIVE AND WE SEE

591
00:25:09,376 --> 00:25:12,212
NECROSIS IN SOME AREAS SO A LOT

592
00:25:12,212 --> 00:25:13,213
OF HISTOLOGICAL HIGH GRADE

593
00:25:13,213 --> 00:25:16,082
FEATURES. WE DID NGS SEQUENCING

594
00:25:16,082 --> 00:25:19,152
ON THIS. AGAIN STILL IDH WILD

595
00:25:19,152 --> 00:25:22,155
TYPE SO IT STILL HAS LOST IDH

596
00:25:22,155 --> 00:25:25,525
MUTATION AND P53 MUTATION IS A

597
00:25:25,525 --> 00:25:27,193
HIGHER BRAIN ALLELE FREQUENCY

598
00:25:27,193 --> 00:25:28,695
WITH OUR HISTOLOGICAL FINDINGS

599
00:25:28,695 --> 00:25:30,997
OF BEING HIGHER ACTIVE TUMOR

600
00:25:30,997 --> 00:25:34,667
BURDEN.  THE METHYLATION

601
00:25:34,667 --> 00:25:36,536
CLASSIFIER IN THIS CASE STILL

602
00:25:36,536 --> 00:25:39,005
GAVE BACK NO MATCH. THE U MAP

603
00:25:39,005 --> 00:25:42,342
DID PUT IT INTO IDH MUTANT HIGH

604
00:25:42,342 --> 00:25:45,011
GRADE ASTRO CYTOMARE GENERAL.

605
00:25:45,011 --> 00:25:46,579
THE U MAP DIMENSIONALITY

606
00:25:46,579 --> 00:25:48,915
REDUCTION NOT AS ROBUST AS THE

607
00:25:48,915 --> 00:25:51,551
METHYLATION CLASSIFIERS AND

608
00:25:51,551 --> 00:25:54,254
STOCHASTIC PLACING SO HARD TO

609
00:25:54,254 --> 00:25:57,090
KNOW TOO MUCH WHAT THIS MEANS

610
00:25:57,090 --> 00:25:59,993
OTHER THAN LOOKS SOME LEVEL

611
00:25:59,993 --> 00:26:03,730
STILL RETAINS EPIGENETIC PROFILE

612
00:26:03,730 --> 00:26:10,336
OF IDH GLIOMA, WE HAVE A LOT OF

613
00:26:10,336 --> 00:26:11,104
ANEUPLOIDY WITH PROGRESSIVE

614
00:26:11,104 --> 00:26:16,242
GLIOMA AND PDJF ONCOGENIC

615
00:26:16,242 --> 00:26:19,612
AMPLIFICATION ON CHROMOSOME 3.

616
00:26:19,612 --> 00:26:21,815
NOW FOR THE FINAL INTEGRATED

617
00:26:21,815 --> 00:26:25,151
PATHOLOGICAL DIAGNOSIS RECURRENT

618
00:26:25,151 --> 00:26:27,353
OR HIGH GRADE GLIOMA, IDH WILD

619
00:26:27,353 --> 00:26:29,923
TYPE BECAUSE LOST THE MUTATION

620
00:26:29,923 --> 00:26:31,057
AND NOT ELSEWHERE CLASSIFIED

621
00:26:31,057 --> 00:26:33,526
BECAUSE THERE IS NO REAL

622
00:26:33,526 --> 00:26:36,596
CRITERIA, IT HASN'T REALLY FIT

623
00:26:36,596 --> 00:26:39,999
THE PROFILE OF ANY SPECIFIC WHO

624
00:26:39,999 --> 00:26:41,935
CLASS AND THIS COMES FROM LOWER

625
00:26:41,935 --> 00:26:46,105
GRADE GLIOMA. AND USUALLY ONE OF

626
00:26:46,105 --> 00:26:49,609
THE QUESTIONS I GET, USUALLY IDH

627
00:26:49,609 --> 00:26:51,711
MUTANT ASTRO CYTOMA WHEN THEY

628
00:26:51,711 --> 00:26:56,249
PROGRESS TO HIGHER GRADE RETAIN

629
00:26:56,249 --> 00:26:57,817
MUTATIONS, THIS DID NOT.  I WANT

630
00:26:57,817 --> 00:26:59,619
TO SHOW ONE SIMILAR TO THIS ONE

631
00:26:59,619 --> 00:27:01,154
WHERE THE PATIENT HAD GRADE 2

632
00:27:01,154 --> 00:27:04,357
ASTRO CYTOMA ID,H MUTANT, UPON

633
00:27:04,357 --> 00:27:07,126
RECURRENCE LOST THE IDH MUTATION

634
00:27:07,126 --> 00:27:10,430
AND GAINED PDFJRN AMPLIFICATION

635
00:27:10,430 --> 00:27:13,333
LIKE THIS PATIENT DID. SO WE

636
00:27:13,333 --> 00:27:16,069
HAVE RECURRING HIGH GRADE

637
00:27:16,069 --> 00:27:18,705
GLIOMA. THEN WE GET TO THE

638
00:27:18,705 --> 00:27:20,874
AUTOPSY POSTMORTEM FINDINGS.

639
00:27:20,874 --> 00:27:22,475
THIS IS GOING TO SHOW A LITTLE

640
00:27:22,475 --> 00:27:23,843
PATHOLOGY FOR THIS, SO THIS IS

641
00:27:23,843 --> 00:27:26,179
WHERE THE FRONTAL LOBE RESECTION

642
00:27:26,179 --> 00:27:28,948
CAVITY IS, YOU CAN SEE IT IS

643
00:27:28,948 --> 00:27:31,484
MORE PALE ON THIS LOWER POWER

644
00:27:31,484 --> 00:27:33,953
HERE. THAT PALE AREA IS FILLED

645
00:27:33,953 --> 00:27:38,658
WITH A LOT OF MACROPHAGES ON HNE

646
00:27:38,658 --> 00:27:40,193
THEN WE CAN CON EQUIPMENT WITH

647
00:27:40,193 --> 00:27:42,362
CD 163 MARKER OF ACTIVATEDDED

648
00:27:42,362 --> 00:27:47,634
MYELOID CELLS. N'T EXTENSIVE BUT

649
00:27:47,634 --> 00:27:49,202
WE DID NOT SEE EVIDENCE OF

650
00:27:49,202 --> 00:27:51,771
CANDIDA IN THESE SLIDES.  SO

651
00:27:51,771 --> 00:27:53,940
BASICALLY KIND OF LIKE THIS

652
00:27:53,940 --> 00:27:55,475
CHRONIC INFARCT TYPE SITUATION

653
00:27:55,475 --> 00:27:57,644
YOU GET WHEN THERE'S BEEN TISSUE

654
00:27:57,644 --> 00:28:01,414
RESECTED.  ADJACENT TO THAT IT

655
00:28:01,414 --> 00:28:04,717
IS LIKE THE FIRST SET OF IMAGES

656
00:28:04,717 --> 00:28:06,619
I SHOWED IT IS MINIMALLY

657
00:28:06,619 --> 00:28:08,021
ATYPICAL, THERE IS SOME

658
00:28:08,021 --> 00:28:11,791
SCATTERED ATYPICAL CELLS. DID

659
00:28:11,791 --> 00:28:14,961
LOOK A LITTLE WHEN WE SAMPLE

660
00:28:14,961 --> 00:28:15,595
THROUGHOUT THROUGHOUT THE BRAIN

661
00:28:15,595 --> 00:28:16,829
DEEPER IN THE THALAMUS SAW

662
00:28:16,829 --> 00:28:18,731
SCATTERED ATYPICAL CELLS IN A

663
00:28:18,731 --> 00:28:21,301
SINGLE MITOSIS WHICH IS KNOWN

664
00:28:21,301 --> 00:28:24,170
WHEN YOU GO AND LOOK AT AUTOPSY

665
00:28:24,170 --> 00:28:29,275
SPECIMENS OF DIFFUSE GLIOOWE MAS

666
00:28:29,275 --> 00:28:30,810
WE GET SINGLE CELLS THROUGHOUT

667
00:28:30,810 --> 00:28:33,813
THE CNS NOT MAKE PICKED UP ON

668
00:28:33,813 --> 00:28:35,381
RADIOGRAPHIC EXAMS SO I WANTED

669
00:28:35,381 --> 00:28:37,984
TO SHOW THIS EXAMPLE. THE FINAL

670
00:28:37,984 --> 00:28:40,587
NEUROPATHOLOGICAL DIAGNOSIS IS

671
00:28:40,587 --> 00:28:41,988
PREDOMINANTLY REACTIVE CHANGES P

672
00:28:41,988 --> 00:28:43,890
WITH RESIDUAL GLIOMA. I WASN'T

673
00:28:43,890 --> 00:28:46,426
ABLE TO GET PICTURES BUT UPON

674
00:28:46,426 --> 00:28:48,628
GROSS EXAMINATION WE CAESAR

675
00:28:48,628 --> 00:28:50,964
BRAILLE DEMANDS NOTCHING

676
00:28:50,964 --> 00:28:54,300
CONSISTENT WITH A TRANSTENTORIAL

677
00:28:54,300 --> 00:28:55,868
LEARNIATION. ONE OF THE FACTORS

678
00:28:55,868 --> 00:29:00,106
IN PATIENT PASSING. SO OVERALL,

679
00:29:00,106 --> 00:29:03,576
WE HAVE TIME LINE OF IDH MUTANT

680
00:29:03,576 --> 00:29:07,580
ASTRO CYTOMA WITH LONG SURVIVAL,

681
00:29:07,580 --> 00:29:10,950
BECAME VERY RECURRENT HIGH GRADE

682
00:29:10,950 --> 00:29:12,852
GLIOMA WITH UNUSUAL GENETIC AND

683
00:29:12,852 --> 00:29:15,054
EPIGENETIC FEATURES BUT

684
00:29:15,054 --> 00:29:16,289
OTHERWISE LOOKED LIKE WHEN IT

685
00:29:16,289 --> 00:29:20,059
GOT THE RADIATION PRIOR TO HIS

686
00:29:20,059 --> 00:29:22,028
PASSING THAT IT LOOKED LIKE THAT

687
00:29:22,028 --> 00:29:23,963
WOULD HAVE CONTROLLED THE

688
00:29:23,963 --> 00:29:26,799
GLIOMA. SO THAT IS IT FOR THE

689
00:29:26,799 --> 00:29:31,938
PATHOLOGY. NOWLY TURN IT TO DR.

690
00:29:31,938 --> 00:29:33,373
BROWN TO TALK ASSOCIATED

691
00:29:33,373 --> 00:29:37,310
BIOLOGY.

692
00:29:37,310 --> 00:29:41,648
>> THANKS PJ. THIS IS VERY

693
00:29:41,648 --> 00:29:42,548
INTERESTING AND COMPLEX CASE. 

694
00:29:42,548 --> 00:29:48,454
I'M GOING TO SEGUE HERE INTO

695
00:29:48,454 --> 00:29:49,856
SOME OF THE BIOLOGICAL

696
00:29:49,856 --> 00:29:51,724
IMPLICATIONS AND TIE THAT INTO

697
00:29:51,724 --> 00:29:53,159
SOME OF THE THINGS I WORK ON IN

698
00:29:53,159 --> 00:29:56,095
THE LAB. BEFORE I DO, I KNOW

699
00:29:56,095 --> 00:29:58,164
THIS IS A COMPLEX CASE.  DOES

700
00:29:58,164 --> 00:29:59,499
ANYBODY HAVE QUESTIONS ABOUT THE

701
00:29:59,499 --> 00:30:02,602
CASE, THE IMAGING OR PATHOLOGY

702
00:30:02,602 --> 00:30:03,936
THAT'S BEEN PREVIOUSLY

703
00:30:03,936 --> 00:30:09,409
PRESENTED? SO ONE OF THE THINGS

704
00:30:09,409 --> 00:30:11,277
I DO WANT TO POINT OUT IS THAT

705
00:30:11,277 --> 00:30:13,613
YOU SAW THE TIME LINE ON THE

706
00:30:13,613 --> 00:30:14,947
LAST SLIDE WHERE THE PATIENT

707
00:30:14,947 --> 00:30:17,183
INITIALLY GOT DIAGNOSED WITH

708
00:30:17,183 --> 00:30:19,619
ESSENTIAL WILL I LOW GRADE

709
00:30:19,619 --> 00:30:26,059
GLIOMA IN 2011. THEN THEY HAD

710
00:30:26,059 --> 00:30:28,094
RECURRENCE OF SOMETHING THAT HAD

711
00:30:28,094 --> 00:30:31,431
LAST -- THAT IDH MUTATION AND SO

712
00:30:31,431 --> 00:30:33,833
ON IN JUNE BUT BY DECEMBER THEY

713
00:30:33,833 --> 00:30:37,704
HAD PROGRESSED SO MUCH THAT THEY

714
00:30:37,704 --> 00:30:41,074
DIED. SO THAT'S KIND OF

715
00:30:41,074 --> 00:30:42,275
IMPLICATIONS HERE IN TERMS OF

716
00:30:42,275 --> 00:30:46,879
WHEN WE THINK ABOUT

717
00:30:46,879 --> 00:30:48,214
GLIOBLASTOMA, THE HIGH GRADE

718
00:30:48,214 --> 00:30:50,283
GLIOMAS WE TALK ABOUT. AND THE

719
00:30:50,283 --> 00:30:52,719
FACT THAT NOT ONLY ARE THEY

720
00:30:52,719 --> 00:30:55,788
UNIVERSALLY FATAL, BUT REALLY

721
00:30:55,788 --> 00:30:58,458
AGGRESSIVE. AND THAT TIME LINE

722
00:30:58,458 --> 00:30:59,892
IS NOT OUT OF THE ORDINARY.

723
00:30:59,892 --> 00:31:01,060
THAT'S KIND OF WHAT WE SEE. SO

724
00:31:01,060 --> 00:31:03,930
IT IS REALLY IMPORTANT THAT WE

725
00:31:03,930 --> 00:31:05,031
STILL KEEP ENERGY ON THIS

726
00:31:05,031 --> 00:31:06,365
DISEASE AND WE HAVEN'T MADE A

727
00:31:06,365 --> 00:31:08,267
LOT OF PROGRESS HERE. I WILL

728
00:31:08,267 --> 00:31:10,603
TALK ABOUT SOME OF THAT AS I GO

729
00:31:10,603 --> 00:31:13,439
ON. SEGUEING TO THE BIOLOGY. SO

730
00:31:13,439 --> 00:31:17,076
WE ARE GOING TO TALK ABOUT THIS

731
00:31:17,076 --> 00:31:21,180
PATIENT HAD ULTIMATELY INFECTION

732
00:31:21,180 --> 00:31:25,752
WITH CANDIDA PEREPSILOSIS. SO

733
00:31:25,752 --> 00:31:28,855
THAT IS A FUNGUS THAT IS ON ALL

734
00:31:28,855 --> 00:31:31,190
OUR SKINS. AND LIVES IN OUR GI

735
00:31:31,190 --> 00:31:33,226
TRACT. TYPICALLY NOT SOMETHING

736
00:31:33,226 --> 00:31:35,762
THAT CAUSES FATAL INFECTION

737
00:31:35,762 --> 00:31:38,297
UNLESS YOU ARE

738
00:31:38,297 --> 00:31:40,099
IMMUNOCOMPROMISED. SO AS I WILL

739
00:31:40,099 --> 00:31:45,171
TALK ABOUT HERE, CANCER IN

740
00:31:45,171 --> 00:31:46,839
GENERAL BUT GLIAL BLASTOMA IN

741
00:31:46,839 --> 00:31:52,912
PARTICULAR ARE ADEPT AT LOWERING

742
00:31:52,912 --> 00:31:55,915
YOUR ABILITY TO MOUNT AN IMMUNE

743
00:31:55,915 --> 00:31:57,250
RESPONSE AGAINST TUMOR. SO THERE

744
00:31:57,250 --> 00:31:59,485
IS TUMOR MEDIATED

745
00:31:59,485 --> 00:32:00,486
IMMUNOSUPPRESSION THAT IS A

746
00:32:00,486 --> 00:32:06,225
REALLY BIG FEATURE OF

747
00:32:06,225 --> 00:32:07,160
GLIOBLASTOMAS, IN FACT AUSTIN

748
00:32:07,160 --> 00:32:09,362
AND OTHERS HAVE WRITTEN ABOUT

749
00:32:09,362 --> 00:32:13,566
SOMEBODY WITH HIGH GRADE OWE MA,

750
00:32:13,566 --> 00:32:17,770
LOOKS LIKE -- GLIOMA, LOOKS LIKE

751
00:32:17,770 --> 00:32:19,906
SOMEBODY WITH AIDS IN TERMS OF

752
00:32:19,906 --> 00:32:21,741
T-CELL LYMPHOPENIA, AND THE

753
00:32:21,741 --> 00:32:23,876
HALLMARK OF AIDS BEING

754
00:32:23,876 --> 00:32:24,877
OPPORTUNISTIC INFECTIONS LIKE

755
00:32:24,877 --> 00:32:27,547
THIS. SO THAT IS KIND OF ONE OF

756
00:32:27,547 --> 00:32:30,449
THE BIG AREAS MY LAB STUDIES. SO

757
00:32:30,449 --> 00:32:34,554
WE DO THIS BY TRYING TO

758
00:32:34,554 --> 00:32:36,355
UNDERSTAND SIGNALING THROUGH

759
00:32:36,355 --> 00:32:38,224
THIS ORGANELLE THAT ESSENTIALLY

760
00:32:38,224 --> 00:32:40,359
ALL OF OUR CELLS HAVE, NUCLEATED

761
00:32:40,359 --> 00:32:47,967
CELLS ANYWAY, HAVE A PRY PLAYERY

762
00:32:47,967 --> 00:32:51,170
CILIUM. IT IS KIND OFs SEW

763
00:32:51,170 --> 00:32:52,605
TEARIC SO I WILL SPEND A LITTLE

764
00:32:52,605 --> 00:32:55,341
TIME TALKING ABOUT THIS, IT IS

765
00:32:55,341 --> 00:32:56,776
DIDN'T THAN THE CILIA IN YOUR

766
00:32:56,776 --> 00:32:58,644
TRACHEA THAT MOVE THINGS ALONG

767
00:32:58,644 --> 00:33:00,646
OR OTHER MOW TILE CILIA LIKE IN

768
00:33:00,646 --> 00:33:04,450
SPERM. THESE ARE NON-MOTILE

769
00:33:04,450 --> 00:33:07,687
CILIA WITH 9 PLUS 0 ARRANGEMENT

770
00:33:07,687 --> 00:33:15,695
YOU CAN SEE 9 MICROTUBULE DUB

771
00:33:15,695 --> 00:33:17,563
DUBLET. WHAT WE KNOW NOW ABOUT

772
00:33:17,563 --> 00:33:20,533
PRIMARY CILIA, THEY ARE

773
00:33:20,533 --> 00:33:23,202
IMPORTANT ZIP CODES IN THE CELL

774
00:33:23,202 --> 00:33:26,105
WHERE A LOT OF IMPORTANT

775
00:33:26,105 --> 00:33:27,506
CANONICAL SIGNAL TRANSDUCTIONS

776
00:33:27,506 --> 00:33:32,278
PATHWAYS THAT P HAPPEN. SO THE

777
00:33:32,278 --> 00:33:34,814
PROTOTYPE IS SONIC HEDGEHOG

778
00:33:34,814 --> 00:33:36,716
WHICH REQUIRES PRIMARY SILL YUM

779
00:33:36,716 --> 00:33:40,686
TO WORK. SO -- CILIUM TO WORK.

780
00:33:40,686 --> 00:33:46,225
WHEN THERE IS A PRIMARY CILIUM

781
00:33:46,225 --> 00:33:48,861
YOU GET ACTIVATION PATHWAY AFTER

782
00:33:48,861 --> 00:33:50,863
SMOOTHEN GOES UP AND IT COMES TO

783
00:33:50,863 --> 00:33:52,431
THE NUCLEUS AND YOU GET

784
00:33:52,431 --> 00:33:53,299
ACTIVATION OF HEDGEHOG

785
00:33:53,299 --> 00:33:56,335
SIGNALING. IN MANY B A SENSE OF

786
00:33:56,335 --> 00:33:58,204
CILIA THIS ACTIVATION OF

787
00:33:58,204 --> 00:33:59,538
SMOOTHEN CAN OCCUR AND THE

788
00:33:59,538 --> 00:34:01,007
GLIOMA PROTEINS DON'T GET

789
00:34:01,007 --> 00:34:02,341
ACTIVATE AND YOU DON'T GET THAT

790
00:34:02,341 --> 00:34:04,243
TO WORK. IN ADDITION TO

791
00:34:04,243 --> 00:34:06,245
HEDGEHOG, THIS IS JUST ON THE

792
00:34:06,245 --> 00:34:09,215
RIGHT, A SMATTERING OF ALL THE

793
00:34:09,215 --> 00:34:12,318
DIFFERENT SIGNALING CASCADES

794
00:34:12,318 --> 00:34:14,754
THAT ARE WELL WORKED OUT TO

795
00:34:14,754 --> 00:34:17,723
REQUIRE PRIMARY CILIA TO CONTROL

796
00:34:17,723 --> 00:34:19,425
THEM. IT IS DIFFERENT WAYS.  IT

797
00:34:19,425 --> 00:34:21,427
IS NOT THE CASE WHERE FOR

798
00:34:21,427 --> 00:34:25,798
EXAMPLE, ALL OF THESE REQUIRE

799
00:34:25,798 --> 00:34:29,001
CILIUM. WINT SIGNALING IF THERE

800
00:34:29,001 --> 00:34:31,404
ARE DEVELOPMENTAL BIOLOGISTS IN

801
00:34:31,404 --> 00:34:34,040
THE ROOM WINT SIGNALING IS VERY

802
00:34:34,040 --> 00:34:36,943
IMPORTANT IN NEURAL TUBE

803
00:34:36,943 --> 00:34:38,077
DEVELOPMENT, WINT SIGNALING IS

804
00:34:38,077 --> 00:34:40,680
INHIBITED BY RENT PRESENCE OF

805
00:34:40,680 --> 00:34:42,281
CILIUM. SO COMPLEX RELATIONSHIPS

806
00:34:42,281 --> 00:34:45,885
BUT IN OUR PATIENT WE SAW

807
00:34:45,885 --> 00:34:50,323
AMPLIFICATION OF THE PDGFRA

808
00:34:50,323 --> 00:34:51,457
RECEPTOR TYPE ARE A. FOR EXAMPLE

809
00:34:51,457 --> 00:34:55,094
THIS IS A VERY CILIA DEPENDENT

810
00:34:55,094 --> 00:34:57,229
PATHWAY. SO LOTS OF IMPLICATIONS

811
00:34:57,229 --> 00:35:02,234
HERE. SO AGAIN GLIOBLASTOMA, IT

812
00:35:02,234 --> 00:35:04,904
IS A SUCKY DISEASE. LIKE I SAID

813
00:35:04,904 --> 00:35:06,872
INVARIABLY FATAL. ONE THING I

814
00:35:06,872 --> 00:35:10,710
WANT TO POINT OUT, AGAIN, GOING

815
00:35:10,710 --> 00:35:12,845
WITH THE WHAT OCCURRED IN OUR

816
00:35:12,845 --> 00:35:14,413
PATIENT. THIS IS STANDARD OF

817
00:35:14,413 --> 00:35:17,817
CARE. AND SO I KNOW THAT DR.

818
00:35:17,817 --> 00:35:19,185
LAWS MENTIONED THAT A LITTLE

819
00:35:19,185 --> 00:35:23,456
BIT, BUT THESE PATIENTS COME IN,

820
00:35:23,456 --> 00:35:26,425
THE FIRST ELEMENT AND TREATMENT

821
00:35:26,425 --> 00:35:29,195
IS USUALLY WHAT WE SAY IS

822
00:35:29,195 --> 00:35:31,664
MAXIMAL SAFE RESECTION. SO THE

823
00:35:31,664 --> 00:35:32,798
MOST BRAIN YOU CAN SAFELY TAKE

824
00:35:32,798 --> 00:35:34,700
OUT, THAT'S THE FIRST STEP.

825
00:35:34,700 --> 00:35:37,236
WITHOUT HURTING THEM TOO MUCH. 

826
00:35:37,236 --> 00:35:38,804
THE NEXT STEP IS THAT THEY WILL

827
00:35:38,804 --> 00:35:40,806
THEN GO ON TO THIS ONE MONTH

828
00:35:40,806 --> 00:35:44,076
PERIOD OF DAILY RADIATION WITH

829
00:35:44,076 --> 00:35:45,177
CHEMOTHERAPY FOLLOWED BY SIX

830
00:35:45,177 --> 00:35:47,213
MONTHS OF CHEMOTHERAPY. TOGETHER

831
00:35:47,213 --> 00:35:49,682
THAT IS THE TWO PROTOCOL. AFTER

832
00:35:49,682 --> 00:35:51,917
THAT, WHAT YOU GET IS THIS

833
00:35:51,917 --> 00:35:53,219
DIFFERENCE HERE IN LIFE

834
00:35:53,219 --> 00:35:54,253
EXPECTANCY BETWEEN THE RED AND

835
00:35:54,253 --> 00:35:57,490
THE BLUE.  SO COUPLE OF MONTHS.

836
00:35:57,490 --> 00:36:00,493
PEOPLE WHO DON'T GET THAT, DIE

837
00:36:00,493 --> 00:36:01,460
RELATIVELY SOON WITHIN WEEKS.

838
00:36:01,460 --> 00:36:04,363
YOU CAN EXTEND THAT TO A FEW

839
00:36:04,363 --> 00:36:06,132
MONTHS WITHOUT REALLY HERCULEAN

840
00:36:06,132 --> 00:36:08,901
TREATMENT. AND I WANT TO AGAIN

841
00:36:08,901 --> 00:36:11,937
REITERATE HERE IS THIS IDEA THAT

842
00:36:11,937 --> 00:36:14,840
THE IMMUNOSUPPRESSION LIMITS A

843
00:36:14,840 --> 00:36:16,809
LOT OF TREATMENT INCLUDING THE

844
00:36:16,809 --> 00:36:19,278
WHOLE NEW CLASS OF DRUGS FOR

845
00:36:19,278 --> 00:36:21,080
CANCER, CALLED IMMUNOTHERAPIES

846
00:36:21,080 --> 00:36:22,748
THAT HAVE REVOLUTION AS IORIZE

847
00:36:22,748 --> 00:36:27,053
HOW WE THINK ABOUT OTHER --

848
00:36:27,053 --> 00:36:30,523
REVOLUTIONIZED HOW WE SEE WE SEE

849
00:36:30,523 --> 00:36:32,658
THE ADS ON TV, THOSE ARE CHECK

850
00:36:32,658 --> 00:36:34,427
POINT INHIBITORS THAT BLOCK

851
00:36:34,427 --> 00:36:35,895
CANCER ABILITY TO SUPPRESS THE

852
00:36:35,895 --> 00:36:39,098
IMMUNE SYSTEM AND THOSE DON'T

853
00:36:39,098 --> 00:36:42,635
WORK IN GLIOBLASTOMA. SO THAT A

854
00:36:42,635 --> 00:36:44,236
BIG FUNCTION OF OUR LAB.  THAT'S

855
00:36:44,236 --> 00:36:45,337
MOSTLY WHAT I WILL TALK ABOUT

856
00:36:45,337 --> 00:36:49,775
TODAY.  SO WHAT DO WE KNOW SO

857
00:36:49,775 --> 00:36:54,814
FAR ABOUT THE WAY THIS WORKS?

858
00:36:54,814 --> 00:36:56,348
GLIOBLAHS STOMA, ONE OF THE

859
00:36:56,348 --> 00:36:57,249
FIRST QUESTION YOU SHOULD ASK,

860
00:36:57,249 --> 00:36:59,919
WE ARE NOT TALKING LUNG CANCER

861
00:36:59,919 --> 00:37:02,555
OR BREAST CANCER, WHICH IS

862
00:37:02,555 --> 00:37:04,757
ALREADY IN THE SYSTEMIC

863
00:37:04,757 --> 00:37:05,991
CIRCULATION IN THE SYSTEM, WE

864
00:37:05,991 --> 00:37:10,096
ARE TALKING ABOUT GLIOBLASTOMA,

865
00:37:10,096 --> 00:37:11,897
WHICH ARE ISOLATED TO THE

866
00:37:11,897 --> 00:37:13,232
CENTRAL NERVOUS SYSTEM SO HOW

867
00:37:13,232 --> 00:37:14,600
DOES THAT CAUSE YOUR BONE MARROW

868
00:37:14,600 --> 00:37:17,570
TO BE SUPPRESSED? BECAUSE BY

869
00:37:17,570 --> 00:37:19,371
DEFINITION GLIOBLASTOMAS DON'T

870
00:37:19,371 --> 00:37:20,439
SPREAD OUTSIDE THE CENTRAL

871
00:37:20,439 --> 00:37:22,908
NERVOUS SYSTEM SO WHAT IS THAT

872
00:37:22,908 --> 00:37:25,411
MECHANISM? SO US AND OTHERS

873
00:37:25,411 --> 00:37:27,713
WORKED OUT THAT GLIOBLASTOMAS

874
00:37:27,713 --> 00:37:30,916
LIKE MANY OTHER CANCERS RELEASE

875
00:37:30,916 --> 00:37:34,320
VESICALES CALLED EXTRA CELLULAR

876
00:37:34,320 --> 00:37:36,188
VESICLES. AND ONCE THOSE ARE

877
00:37:36,188 --> 00:37:38,390
RELEASED THE EXTRA CELLULAR

878
00:37:38,390 --> 00:37:40,059
VESICLES RELEASED FROM THE

879
00:37:40,059 --> 00:37:41,594
TUMOR, BUT NOT TUMOR CELLS

880
00:37:41,594 --> 00:37:43,028
THEMSELVES ARE ABLE TO ESCAPE

881
00:37:43,028 --> 00:37:44,897
THE CENTRAL NERVOUS SYSTEM,

882
00:37:44,897 --> 00:37:46,432
ENTER THE SYSTEMIC CIRCULATION. 

883
00:37:46,432 --> 00:37:48,934
WHEN THEY DO THAT, THEN THEY ARE

884
00:37:48,934 --> 00:37:55,374
ABLE TO CAUSE A WHOLE HOST OF

885
00:37:55,374 --> 00:37:57,009
IMMUNE RELATED EVENTS.  ONE

886
00:37:57,009 --> 00:38:00,446
EVENT IMPLICATED IN THE

887
00:38:00,446 --> 00:38:01,814
GLIOBLASTOMA MEDIATED

888
00:38:01,814 --> 00:38:02,681
IMMUNOSUPPRESSION IS THIS

889
00:38:02,681 --> 00:38:04,483
CONVERSION OF YOUR NAIVE

890
00:38:04,483 --> 00:38:06,619
MONOCYTES INTO THESE MYELOID

891
00:38:06,619 --> 00:38:07,920
DERIVED SUPPRESSER CELLS. THOSE

892
00:38:07,920 --> 00:38:11,390
ARE THE MDSCs.  MDSCs IN

893
00:38:11,390 --> 00:38:13,859
TURN ARE ABLE TO AFFECT YOUR

894
00:38:13,859 --> 00:38:16,495
T-CELLS IN TWO WAYS. ONE IS THEY

895
00:38:16,495 --> 00:38:19,064
BLOCK PROLIFERATION AND

896
00:38:19,064 --> 00:38:20,132
EXPANSION OF T-CELLS NECESSARY

897
00:38:20,132 --> 00:38:23,135
FOR YOUR T-CELLS TO TARGET NEW

898
00:38:23,135 --> 00:38:26,639
ANTIGENS, THEY NEED TO REPRODUCE

899
00:38:26,639 --> 00:38:30,543
AND GROW AND MDSCs BLOCK THAT

900
00:38:30,543 --> 00:38:32,545
AND FOR THE, T CELLS AROUND THEY

901
00:38:32,545 --> 00:38:34,280
NEED THE ACTIVATE TO ATTACK THE

902
00:38:34,280 --> 00:38:36,382
ANTIGENS THEY SEE AND THE

903
00:38:36,382 --> 00:38:37,716
MDSCs ALSO BLOCK THAT PROCESS.

904
00:38:37,716 --> 00:38:39,852
SO NOW WHEN THE MDSCs ARE

905
00:38:39,852 --> 00:38:41,453
PRESENT YOU HAVE A LOW T-CELL

906
00:38:41,453 --> 00:38:43,455
COUNT AND T-CELLS PRESENT DON'T

907
00:38:43,455 --> 00:38:45,991
WORK. SO YOU GET THIS DOUBLE

908
00:38:45,991 --> 00:38:51,230
CLAMMWHAMMY. SO THIS IS NOT

909
00:38:51,230 --> 00:38:54,233
NECESSARILY UNIQUE. TO

910
00:38:54,233 --> 00:38:57,970
GLIOBLASTOMA. SO THIS IS FROM A

911
00:38:57,970 --> 00:39:00,539
PRIOR STUDY THAT WAS PUBLISHED

912
00:39:00,539 --> 00:39:02,841
LOOKING AT HEPATOCELLULAR

913
00:39:02,841 --> 00:39:04,610
CARCINOMA, THAT ULTIMATELY YOU

914
00:39:04,610 --> 00:39:09,248
CAN SEE MDSCs GET PRODUCED.

915
00:39:09,248 --> 00:39:10,583
VERY SIMILAR TO THE PRODUCTION

916
00:39:10,583 --> 00:39:13,719
WE TALKED ABOUT PREVIOUSLY. BUT

917
00:39:13,719 --> 00:39:15,754
AND THEN YOU CAN SEE ULTIMATELY

918
00:39:15,754 --> 00:39:18,591
YOUR T-CELLS GET EXHAUSTED. AND

919
00:39:18,591 --> 00:39:20,426
AGAIN, YOU CAN SEE THAT THAT IS

920
00:39:20,426 --> 00:39:21,827
CONSIDERED TO BE MEDIATED BY

921
00:39:21,827 --> 00:39:25,664
THIS PD 1 PDL 1 CHECK POINT, THE

922
00:39:25,664 --> 00:39:27,433
SO CALLED IMMUNE CHECK POINTS

923
00:39:27,433 --> 00:39:28,834
WHICH ARE THE TARGET OF THESE

924
00:39:28,834 --> 00:39:31,170
IMMUNE CHECK POINT INHIBITOR

925
00:39:31,170 --> 00:39:33,172
DRUGS. SO WHAT CAUGHT MY

926
00:39:33,172 --> 00:39:37,643
ATTENTION WHEN I SAW THIS, WAS

927
00:39:37,643 --> 00:39:39,545
THAT IT WAS THOUGHT THIS

928
00:39:39,545 --> 00:39:43,415
MOLECULE HERE CCRK, CELL CYCLE

929
00:39:43,415 --> 00:39:47,486
RELATED KINASE, CDK 20, BECAUSE

930
00:39:47,486 --> 00:39:49,455
IT IS THOUGHT BASED ON

931
00:39:49,455 --> 00:39:51,557
SEQUENCING TO BE IN THE CDC

932
00:39:51,557 --> 00:39:53,092
FAMILY BUT SOMEHOW SITS ATOP

933
00:39:53,092 --> 00:39:58,030
THAT PATHWAY. THAT ULTIMATELY

934
00:39:58,030 --> 00:40:02,401
LEADS TO CONTEXT OF IL 6 IN

935
00:40:02,401 --> 00:40:04,403
HEPATOCELLULAR CARCINOMA, DRIVES

936
00:40:04,403 --> 00:40:05,404
T-CELL PRODUCTION AND EXHAUSTS

937
00:40:05,404 --> 00:40:09,475
YOUR T-CELLS. SO I THOUGHT THAT

938
00:40:09,475 --> 00:40:11,410
WAS SERENDIPITOUS BECAUSE YEARS

939
00:40:11,410 --> 00:40:14,546
EARLIER I CLONED THE FIRST CCRK

940
00:40:14,546 --> 00:40:16,782
MOUSE. SO WHAT WE WERE LOOKING

941
00:40:16,782 --> 00:40:20,986
AT AT THAT TIME WAS

942
00:40:20,986 --> 00:40:23,822
UNDERSTANDING PRIMARY CILIA IN

943
00:40:23,822 --> 00:40:28,594
CONTEXT OF NEURAL DEVELOPMENT.

944
00:40:28,594 --> 00:40:32,698
THIS IS A WILD TYPE MOUSE AT

945
00:40:32,698 --> 00:40:35,734
EMBRYONIC DAY 12.5 COMPARED TO

946
00:40:35,734 --> 00:40:38,804
CCRK KNOCK OUT.  THERE ARE

947
00:40:38,804 --> 00:40:44,009
FEATURES LIKE EXEANCEPHALY. YOU

948
00:40:44,009 --> 00:40:46,578
CAN SEE POLYSYNDACTYLY AND

949
00:40:46,578 --> 00:40:48,747
SKELETAL DEFECTS.  THE MORAL OF

950
00:40:48,747 --> 00:40:51,450
THE STORY, THOSE DEFECTS LOOK

951
00:40:51,450 --> 00:40:53,352
VERY SIMILAR TO WHAT YOU SEE IF

952
00:40:53,352 --> 00:40:55,054
YOU KNOCK OUT SONIC HEDGEHOG IN

953
00:40:55,054 --> 00:40:57,323
A MOUSE.  BUT WE DO KNOW THAT AS

954
00:40:57,323 --> 00:40:59,758
I TOLD YOU HEDGEHOG SIGNALING IS

955
00:40:59,758 --> 00:41:02,094
THE SORT OF PROTOTYPE PATHWAY

956
00:41:02,094 --> 00:41:04,196
FOR WHICH PRIMARY CILIA WERE

957
00:41:04,196 --> 00:41:06,031
KNOWN TO BE IMPORTANT. SO WE

958
00:41:06,031 --> 00:41:08,400
DECIDED TO SAY WHAT HAPPENS TO

959
00:41:08,400 --> 00:41:12,938
PRIMARY CILIA IN OUR CCRK KNOCK

960
00:41:12,938 --> 00:41:14,973
OUTS SO YOU CAN SEE SCANNING

961
00:41:14,973 --> 00:41:17,209
ELECTRON MICROSCOPY HERE,

962
00:41:17,209 --> 00:41:19,044
IMMUNOFLUORESCENCE LOOKING AT R

963
00:41:19,044 --> 00:41:23,215
13B WHICH IS SPECIFIC TO THAT

964
00:41:23,215 --> 00:41:24,416
MICROTUBULE STRUCTURE OF PRIMARY

965
00:41:24,416 --> 00:41:26,752
CILIA AS WELL AS GAMMA TUBULIN,

966
00:41:26,752 --> 00:41:28,721
WHICH STAINS THE BASAL BODY

967
00:41:28,721 --> 00:41:30,389
WHICH THE PRIMARY CILIA EMANATE.

968
00:41:30,389 --> 00:41:33,158
YOU CAN SEE MORPHOLOGICALLY HOW

969
00:41:33,158 --> 00:41:36,028
THEY ARE DIFFERENT. YOU CAN SEE

970
00:41:36,028 --> 00:41:37,496
THE ROUNDED STRUCTURES HERE AND

971
00:41:37,496 --> 00:41:41,266
THIS IS TEM ON THE OTHER SIDES. 

972
00:41:41,266 --> 00:41:42,935
AND IMPORTANTLY WHAT WE WERE

973
00:41:42,935 --> 00:41:44,703
ABLE TO CONFIRM, SO I SHOWEDDED

974
00:41:44,703 --> 00:41:47,072
YOU EARLIER HOW WHEN THE PRIMARY

975
00:41:47,072 --> 00:41:48,774
CILIA ARE PRESENT AND HEDGEHOG

976
00:41:48,774 --> 00:41:52,277
SIGNALING THE WORKING, THAT YOU

977
00:41:52,277 --> 00:41:54,179
GET ACTIVATION OF THESE SO

978
00:41:54,179 --> 00:41:57,449
CALLED GLIOMA PROTEINS. ONE

979
00:41:57,449 --> 00:41:58,817
THICK YOU CAN DO AS READ OUT HOW

980
00:41:58,817 --> 00:42:01,620
WELL THIS IS WORKING IS ASK

981
00:42:01,620 --> 00:42:03,088
WELL, WHAT ABOUT THIS ACTIVATION

982
00:42:03,088 --> 00:42:06,125
OF GLI 1. YOU CAN SO E IN THE

983
00:42:06,125 --> 00:42:09,228
CONTEXT OF THE CRRK KNOCK OUT

984
00:42:09,228 --> 00:42:11,163
YOU CAN'T GET ACTIVATION OF GLI

985
00:42:11,163 --> 00:42:12,931
1 IN THE WAY YOU DO WILD TYPE.

986
00:42:12,931 --> 00:42:15,367
SO WHAT WE FOUND IN A VERY

987
00:42:15,367 --> 00:42:17,936
SEPARATE CONTEXT WAS THAT CCRK

988
00:42:17,936 --> 00:42:20,172
IS IMPORTANT FOR CILIA

989
00:42:20,172 --> 00:42:21,440
MORPHOLOGY AND BECAUSE OF ITS

990
00:42:21,440 --> 00:42:26,345
ROLE IN CILIA MORPHOLOGY, WHEN

991
00:42:26,345 --> 00:42:28,580
ITS LEVELS ARE CHANGED IT

992
00:42:28,580 --> 00:42:29,314
AFFECTS FUNCTION OF PRIMARY

993
00:42:29,314 --> 00:42:33,819
CILIA. SO MAX WORKED ON THIS A

994
00:42:33,819 --> 00:42:35,320
WILD BACK WHERE WE WANTED TO

995
00:42:35,320 --> 00:42:40,793
START EXPLORING IS THIS A CCRK

996
00:42:40,793 --> 00:42:45,664
SPECIFIC THING OR IS THE ROLE OF

997
00:42:45,664 --> 00:42:48,100
SAY CCRK ULTIMATELY LEADING TO

998
00:42:48,100 --> 00:42:50,636
HIGH LEVELS OF IL 6, IS THAT

999
00:42:50,636 --> 00:42:53,205
JUST SOMETHING THAT IS PRIMARY

1000
00:42:53,205 --> 00:42:56,108
CILIA BUT WE SEE THAT THROUGH

1001
00:42:56,108 --> 00:42:57,342
CCRK BECAUSE OF THE AFFECT ON

1002
00:42:57,342 --> 00:42:59,144
THE PRIMARY CILIA.  SO WHAT WE

1003
00:42:59,144 --> 00:43:00,512
DID IS THIS EXPERIMENT WHERE WE

1004
00:43:00,512 --> 00:43:07,653
SAID OKAY, LET'S LOOK AT CCRK

1005
00:43:07,653 --> 00:43:10,055
KNOCK DOWNS, THIS IS A STABLE

1006
00:43:10,055 --> 00:43:11,623
ANTIVIRAL BASE KNOCK DOWN. WE

1007
00:43:11,623 --> 00:43:14,193
CAN LOOK AND SEE ARE PRIMARY

1008
00:43:14,193 --> 00:43:16,462
CILIAING WITH MADE. WE SEE THAT

1009
00:43:16,462 --> 00:43:20,098
THERE IS REDUCTION IN THAT

1010
00:43:20,098 --> 00:43:22,534
PRIMARY CILIA PHENOTYPE. WE CAN

1011
00:43:22,534 --> 00:43:24,870
ASK WHAT HAPPENS TO IL 6 LEVELS

1012
00:43:24,870 --> 00:43:26,672
WHEN WE DO THAT. MOREOVER SO YOU

1013
00:43:26,672 --> 00:43:29,408
CAN SEE HERE THAT WE ARE LOSING

1014
00:43:29,408 --> 00:43:32,177
THE IL 6. SORRY WE ARE LOSING

1015
00:43:32,177 --> 00:43:35,781
PRIMARY CILIA, WHEN WE DO ELISA

1016
00:43:35,781 --> 00:43:39,351
FOR IL 6 WITH CCRK IL 6 IS DOWN

1017
00:43:39,351 --> 00:43:42,387
QUITE A BIT SO CCRK DOES SEEM TO

1018
00:43:42,387 --> 00:43:46,158
HELP TO DRIVE IL 6 PRODUCTION AS

1019
00:43:46,158 --> 00:43:48,360
FOLKS STUDYING HEPATOCELLULAR

1020
00:43:48,360 --> 00:43:50,395
CARCINOMA FOUN FOUND. WHAT WE DD

1021
00:43:50,395 --> 00:43:52,865
HERE IS SAY WHAT IF WE TOOK TWO

1022
00:43:52,865 --> 00:43:54,867
OTHER PROTEINS THAT ARE KNOWN TO

1023
00:43:54,867 --> 00:43:56,235
BE SPECIFIC AND ESSENTIAL FOR

1024
00:43:56,235 --> 00:43:58,103
PRIMARY CILIA MORPHOLOGY, THAT

1025
00:43:58,103 --> 00:44:02,241
ARE UNRELATED TO CCRK? SO WE DID

1026
00:44:02,241 --> 00:44:05,210
THE CAI KNEE SIN MOTOR KIF 3A

1027
00:44:05,210 --> 00:44:08,780
THOUGHT TO BUILD THE -- IT IS A

1028
00:44:08,780 --> 00:44:10,849
FORWARD MOTOR THAT TAKES THE

1029
00:44:10,849 --> 00:44:12,084
MICROTUBULES AND STACKS THEM ON

1030
00:44:12,084 --> 00:44:13,552
TOP OF EACH OTHER SO YOU CAN

1031
00:44:13,552 --> 00:44:18,090
BUILD A PRIMARY CILIA. THEN IFT

1032
00:44:18,090 --> 00:44:23,495
88 IS ONE OF THE MANY INTRAFLAY

1033
00:44:23,495 --> 00:44:25,030
CELLULAR PROTEINS THAT ATTACHES

1034
00:44:25,030 --> 00:44:26,532
AND BRINGS THE CONSIDER GO UP

1035
00:44:26,532 --> 00:44:27,833
NEEDED TO BUILD PRIMARY SILL

1036
00:44:27,833 --> 00:44:30,702
YUM. SO THESE ARE VERY DIFFERENT

1037
00:44:30,702 --> 00:44:33,572
CLASSES OF MOLECULES UNRELATED

1038
00:44:33,572 --> 00:44:35,073
SO THE QUESTION WE ARE TRYING TO

1039
00:44:35,073 --> 00:44:37,809
PROBE IS, IS THIS REALLY A CCRK

1040
00:44:37,809 --> 00:44:39,444
THING OR IS THIS A CILIA THING

1041
00:44:39,444 --> 00:44:42,681
MORE BROADLY? SO WHAT YOU CAN

1042
00:44:42,681 --> 00:44:45,350
SEE IS REGARDLESS OF WHICH

1043
00:44:45,350 --> 00:44:47,920
METHOD WE USE TO BLOCK CILIA

1044
00:44:47,920 --> 00:44:50,355
FORMATION, IL 6 LEVELS GO DOWN

1045
00:44:50,355 --> 00:44:52,558
NONETHELESS. SO TO US THIS LOOKS

1046
00:44:52,558 --> 00:44:55,327
LIKE MORE OF A CILIA MECHANISM

1047
00:44:55,327 --> 00:44:58,297
AS OPPOSED TO SOMETHING THAT IS

1048
00:44:58,297 --> 00:45:01,400
CCRK. SO THEN WE CAN START TO

1049
00:45:01,400 --> 00:45:03,535
BUILD ON OUR MODEL AS WE GO

1050
00:45:03,535 --> 00:45:05,103
ALONG SO NOW WE KNOW THAT THE

1051
00:45:05,103 --> 00:45:09,274
PRIMARY CILIA ARE PRESENT AND

1052
00:45:09,274 --> 00:45:11,310
BECAUSE WE ALREADY KNOW THIS

1053
00:45:11,310 --> 00:45:12,744
DOWNSTREAM STEP WE TALKED ABOUT

1054
00:45:12,744 --> 00:45:15,981
WHERE THE EVs ARE FORMED, IL 6

1055
00:45:15,981 --> 00:45:18,750
ARE PROBABLY NECESSARY, IN THIS

1056
00:45:18,750 --> 00:45:21,753
PROCESS AS WELL TO CONVERT THESE

1057
00:45:21,753 --> 00:45:24,056
NAIVE MONOCYTES TO MDSC AND THE

1058
00:45:24,056 --> 00:45:26,291
REST YOU KNOW. SO THIS GIVES US

1059
00:45:26,291 --> 00:45:28,193
TESTABLE HYPOTHESES. SO BEFORE I

1060
00:45:28,193 --> 00:45:31,830
DO THAT, I WANT TO SHOW YOU THIS

1061
00:45:31,830 --> 00:45:33,799
IMAGE COMES FROM PATIENTS THAT

1062
00:45:33,799 --> 00:45:36,368
ARE RESECTED WITH GLIOBLASTOMA

1063
00:45:36,368 --> 00:45:37,970
WE CAN BRING TO THE LAB AND

1064
00:45:37,970 --> 00:45:39,237
STAIN. THESE ARE REAL THINGS

1065
00:45:39,237 --> 00:45:41,907
THAT YOU CAN SEE. SO WE HAVE

1066
00:45:41,907 --> 00:45:43,442
CONFOCAL MICROSCOPE IN THE LAB

1067
00:45:43,442 --> 00:45:47,212
AND YOU CAN SEE PERICENTRIN

1068
00:45:47,212 --> 00:45:49,982
WHICH STAINS THE BASAL BODY AND

1069
00:45:49,982 --> 00:45:52,250
YOU CAN SEE ACETYLATED ALPHA

1070
00:45:52,250 --> 00:45:53,952
TUBULIN. YOU CAN SEE THE

1071
00:45:53,952 --> 00:45:55,621
90-DEGREE RELATIONSHIP, YOU CAN

1072
00:45:55,621 --> 00:45:59,858
SEE THE EXINANENE GROWING OUT OF

1073
00:45:59,858 --> 00:46:02,094
THE CELL BODY WITH THE NUCLEUS

1074
00:46:02,094 --> 00:46:06,331
AND THAT IS WHAT I'M CALLING A

1075
00:46:06,331 --> 00:46:09,267
PRIMARY CILIUMM. WE TOOK A

1076
00:46:09,267 --> 00:46:10,602
SIMILAR APPROACH TO SAY IF WE

1077
00:46:10,602 --> 00:46:15,607
DID WHAT WE DID BEFORE FOR IL 6

1078
00:46:15,607 --> 00:46:18,043
YOU CANEE CCRK AND SEE THE CILIA

1079
00:46:18,043 --> 00:46:18,710
FREQUENCY, THE FREQUENCY IS

1080
00:46:18,710 --> 00:46:20,746
DOWN. SO THE QUESTION BECOMES WE

1081
00:46:20,746 --> 00:46:23,248
KNOW WHERE WE BLOCK CILIA IL 6

1082
00:46:23,248 --> 00:46:25,250
GOES DOWN BUT WHAT HAPPENS TO

1083
00:46:25,250 --> 00:46:28,186
THE MYELOID DERIVED SUPPRESSER

1084
00:46:28,186 --> 00:46:30,889
CELLS? ? DO THOSE GO DOWN? WHAT

1085
00:46:30,889 --> 00:46:34,826
YOU CAN SEE IS YES. WHEN YOU

1086
00:46:34,826 --> 00:46:37,295
BLOCK THE PRIMARY CILIA

1087
00:46:37,295 --> 00:46:38,630
REGARDLESS OF THE METHOD USED TO

1088
00:46:38,630 --> 00:46:41,700
BLOCK IT, YOU CAN SEE A HUGE

1089
00:46:41,700 --> 00:46:44,002
REDUCTION IN THE MDSC

1090
00:46:44,002 --> 00:46:45,570
POPULATION.  HERE WE ARE USING

1091
00:46:45,570 --> 00:46:46,705
RADIATION BECAUSE WE KNOW THAT

1092
00:46:46,705 --> 00:46:48,740
WHEN YOU TAKE THESE CELLS, THESE

1093
00:46:48,740 --> 00:46:51,276
BRAIN TUMOR CELLS YOU RADIATE

1094
00:46:51,276 --> 00:46:53,311
THEM YOU CAN SEE AT BASELINE IN

1095
00:46:53,311 --> 00:46:54,913
THE CONTROL GROUP A BIG

1096
00:46:54,913 --> 00:46:56,682
INDUCTIONS IN THE MDSC

1097
00:46:56,682 --> 00:46:58,250
POPULATION. SO EASIER TO STUDY

1098
00:46:58,250 --> 00:46:59,418
AND SEE THE DIFFERENCE IF THERE

1099
00:46:59,418 --> 00:47:01,153
IS ONE. SO THAT'S WHY WE DID

1100
00:47:01,153 --> 00:47:02,487
THAT OVER HERE. YOU CAN SEE

1101
00:47:02,487 --> 00:47:05,323
THERE'S HUGE REDUCTION IN THAT

1102
00:47:05,323 --> 00:47:07,526
UPREGULATION OF MDSCs IN

1103
00:47:07,526 --> 00:47:11,263
RESPONSE TO TUMOR CELLS. THERE

1104
00:47:11,263 --> 00:47:13,298
IS A REDUCTION IN THAT IF YOU

1105
00:47:13,298 --> 00:47:14,800
BLOCK CILIA REGARDLESS HOW YOU

1106
00:47:14,800 --> 00:47:16,601
DO THIS GENETICALLY. THEN

1107
00:47:16,601 --> 00:47:18,003
IMPORTANTLY THEN, IF WE SAY THAT

1108
00:47:18,003 --> 00:47:23,675
THE MDSCs ARE SUPPOSED TO

1109
00:47:23,675 --> 00:47:25,444
BLOCK THE T-CELLS, IN IN TERMS

1110
00:47:25,444 --> 00:47:29,014
OF PROLIFERATION OF FUNCTION WE

1111
00:47:29,014 --> 00:47:35,253
CAN THEN DO -- WE CAN THEN DO

1112
00:47:35,253 --> 00:47:38,156
ASSAYS TO ASK ARE THE LEVELS OF

1113
00:47:38,156 --> 00:47:40,425
THE T-CELLS RESTORED? SO AGAIN

1114
00:47:40,425 --> 00:47:42,094
YOU CAN SEE SAME IDEA HERE THAT

1115
00:47:42,094 --> 00:47:43,729
IN THE CONTROL SETTING YOU ADD

1116
00:47:43,729 --> 00:47:48,467
THE TUMOR, T-CELLS PROLIFERATION

1117
00:47:48,467 --> 00:47:50,969
FALLS OFF BUT IF YOU BLOCK CILIA

1118
00:47:50,969 --> 00:47:52,971
T-CELL PROLIFERATION IS

1119
00:47:52,971 --> 00:47:55,574
RESTORED, DOESN'T MATTER WHETHER

1120
00:47:55,574 --> 00:47:58,176
CCRK OR UNRELATED STRUCTURAL

1121
00:47:58,176 --> 00:48:01,747
NON-KINASE PROTEIN. SO THEN THE

1122
00:48:01,747 --> 00:48:03,982
QUESTION WAS IS THIS ACTUALLY

1123
00:48:03,982 --> 00:48:06,318
MEDIATED THROUGH IL 6? IS THIS

1124
00:48:06,318 --> 00:48:08,787
HAPPENING BECAUSE IL 6 IS LOW

1125
00:48:08,787 --> 00:48:12,357
AND WHAT HAPPENS IF WE BLOCK THE

1126
00:48:12,357 --> 00:48:15,060
CILIA BUT ACTUALLY RESTORE IL 6

1127
00:48:15,060 --> 00:48:17,229
LEVELS? SO THIS IS EXACTLY WHAT

1128
00:48:17,229 --> 00:48:19,331
WE ARE TRYING TO DO HERE. THE

1129
00:48:19,331 --> 00:48:23,268
MORAL OF THIS STORY IS THAT EVEN

1130
00:48:23,268 --> 00:48:25,470
FOLLOWING BLOCKADE OF CILIA, IF

1131
00:48:25,470 --> 00:48:29,241
YOU RESTORE WITH EXOGENOUS IL 6

1132
00:48:29,241 --> 00:48:30,976
YOU CAN TO SOME DEGREE

1133
00:48:30,976 --> 00:48:33,378
CIRCUMVENT THAT REDUCTION IN THE

1134
00:48:33,378 --> 00:48:35,447
MDSCs AND EVEN IN ABSENCE OF

1135
00:48:35,447 --> 00:48:41,086
CILIA, RESTORING IL 6 CAN

1136
00:48:41,086 --> 00:48:44,923
INCREASE YOUR MDSC LEVELS NOT

1137
00:48:44,923 --> 00:48:46,658
QUITE BACK TO NORMAL BUT

1138
00:48:46,658 --> 00:48:48,059
INCREASE THEM. UP HERE AS I

1139
00:48:48,059 --> 00:48:53,799
SHOWED YOU, ULTIMATELY PDL 1 IS

1140
00:48:53,799 --> 00:48:57,569
THE CONNECTOR PD 1 AND PDL 1 IS

1141
00:48:57,569 --> 00:49:00,472
THE CONNECTOR TO ALLOW MDSCs

1142
00:49:00,472 --> 00:49:02,841
TO HAVE THE IMPACT ON T-CELLS SO

1143
00:49:02,841 --> 00:49:04,376
WE ARE TRYING TO UNDERSTAND AND

1144
00:49:04,376 --> 00:49:05,877
WE HAVE SHOWN PREVIOUSLY IN

1145
00:49:05,877 --> 00:49:09,381
PRIOR PUBLICATION IF YOU BLOCK

1146
00:49:09,381 --> 00:49:11,616
PDL 1 MDSC LEVELS DECREASE AS

1147
00:49:11,616 --> 00:49:12,651
WELL SO WE WANTED TO UNDERSTAND

1148
00:49:12,651 --> 00:49:16,588
WHAT HAPPENS IF YOU ARE ALSO

1149
00:49:16,588 --> 00:49:20,458
BLOCKING PDL 1 AS YOU ARE

1150
00:49:20,458 --> 00:49:22,093
BLOCKING IL 6. YOU CAN SEE THAT

1151
00:49:22,093 --> 00:49:24,362
THAT COMBINATION LEADS TO THE

1152
00:49:24,362 --> 00:49:26,464
LOWEST REDUCTION HERE IN THE

1153
00:49:26,464 --> 00:49:28,967
MDSC LEVELS.  ALL RIGHT. SO THIS

1154
00:49:28,967 --> 00:49:30,902
IS ALL COOL BUT SO WHAT? IS THIS

1155
00:49:30,902 --> 00:49:33,872
SOMETHING THAT'S RELEVANT TO THE

1156
00:49:33,872 --> 00:49:35,006
PATIENT WE ARE LOOKING AT IN

1157
00:49:35,006 --> 00:49:36,842
THIS STUDY? AND THE ANSWER IS

1158
00:49:36,842 --> 00:49:39,945
YES. SO WHAT WE DID HERE, WE

1159
00:49:39,945 --> 00:49:43,281
WENT TO THE BLOOD BANK HERE, AND

1160
00:49:43,281 --> 00:49:45,317
WERE ABLE THE GET BLOOD THEN

1161
00:49:45,317 --> 00:49:46,885
COMPARE THIS TO BLOOD THAT I

1162
00:49:46,885 --> 00:49:48,720
TAKE FROM PATIENTS IN THE

1163
00:49:48,720 --> 00:49:51,223
OPERATING ROOM. AND ASK WELL,

1164
00:49:51,223 --> 00:49:53,792
WHAT IF WE LOOKED FOR MDSCs

1165
00:49:53,792 --> 00:49:55,794
USING FLOW CYTOMETRY? ARE WE

1166
00:49:55,794 --> 00:49:58,597
SEEING THESE MDSCs IN THE

1167
00:49:58,597 --> 00:49:59,564
BLOOD OF OUR PATIENT?

1168
00:49:59,564 --> 00:50:01,633
THIS IS SYSTEMIC BLOOD, NOT

1169
00:50:01,633 --> 00:50:04,069
BLOOD FROM THE BRAIN. YOU CAN

1170
00:50:04,069 --> 00:50:05,804
SEE IN OUR PATIENT THERE IS IS

1171
00:50:05,804 --> 00:50:10,041
ACTIVE MDSCs THAT ARE PRETTY

1172
00:50:10,041 --> 00:50:11,376
ABUNDANT AND MEASURABLE.  THE

1173
00:50:11,376 --> 00:50:12,811
OTHER QUESTION, WHAT ABOUT THE

1174
00:50:12,811 --> 00:50:15,180
MECHANISMS AND THESE MACHINERY

1175
00:50:15,180 --> 00:50:18,717
SUCH AS KIF 3 AND CCRK, CAN WE

1176
00:50:18,717 --> 00:50:20,185
SEE THOSE IN THE TUMOR?

1177
00:50:20,185 --> 00:50:21,753
THIS THE IMMUNOHISTOCHEMISTRY

1178
00:50:21,753 --> 00:50:25,457
DONE BY PJ, THAT WE CAN ACTUALLY

1179
00:50:25,457 --> 00:50:29,060
SEE THESE MACHINE AND SAY THEY

1180
00:50:29,060 --> 00:50:31,463
ARE THERE AND THEY ARE PRESENT

1181
00:50:31,463 --> 00:50:32,764
AND WE HAVE THIS THAT IS

1182
00:50:32,764 --> 00:50:37,035
INCREASED. SO WITH THAT BEING

1183
00:50:37,035 --> 00:50:39,337
SAID, WE THEN SAID LET'S LOOK AT

1184
00:50:39,337 --> 00:50:40,839
A MOUSE MODEL OF THE DISEASE. T

1185
00:50:40,839 --> 00:50:47,078
SO DISEASE. SOIF YOU TAKE -- YOE

1186
00:50:47,078 --> 00:50:48,513
WITH IMMUNE SYSTEM TO STUDY

1187
00:50:48,513 --> 00:50:49,848
IMPACT OF TUMOR ON IMMUNE

1188
00:50:49,848 --> 00:50:54,619
SYSTEM. SO WE HAVE A MOUSE MODEL

1189
00:50:54,619 --> 00:50:57,989
OF GLIOBLASTOMAS USING GL 261

1190
00:50:57,989 --> 00:51:00,125
CELLS AND WE CAN DO ORTHO TOPIC

1191
00:51:00,125 --> 00:51:01,326
TRANSPLANTATION INTO THE MOUSE.

1192
00:51:01,326 --> 00:51:03,228
SO WE TAKE THE BRAIN TUMOR

1193
00:51:03,228 --> 00:51:04,429
CELLS, INJECT INTO THE MOUSE. 

1194
00:51:04,429 --> 00:51:07,065
WHEN WE DO THAT YOU CAN SEE JUST

1195
00:51:07,065 --> 00:51:11,002
-- THIS IS THE MOUSE WITH NO

1196
00:51:11,002 --> 00:51:12,504
TUMOR JUST A SHUNT SURGERY, SO

1197
00:51:12,504 --> 00:51:14,172
WE NORMALIZE THAT TO ONE HERE

1198
00:51:14,172 --> 00:51:17,242
BUT WHEN WE INJECT TUMOR CELLS

1199
00:51:17,242 --> 00:51:20,478
YOU CAN SEE THIS MDSC

1200
00:51:20,478 --> 00:51:24,049
SPECIFICALLY THIS MONOSITIC MDSC

1201
00:51:24,049 --> 00:51:27,252
POPULATION GOES UP OVER TWOFOLD.

1202
00:51:27,252 --> 00:51:30,121
BUT IF IN THE CELLS YOU ACTUALLY

1203
00:51:30,121 --> 00:51:32,057
BLOCK ANY ONE OF THOSE

1204
00:51:32,057 --> 00:51:33,491
COMPONENTS NECESSARY FOR PRIMARY

1205
00:51:33,491 --> 00:51:36,761
CILIA FORMATION, PRIOR TO THE

1206
00:51:36,761 --> 00:51:38,330
IMPLANTATION, COMPARED TO A

1207
00:51:38,330 --> 00:51:40,765
SCRAMBLE CONTROL YOU CAN SEE THE

1208
00:51:40,765 --> 00:51:42,567
MDSC POPULATION GOES DOWN.

1209
00:51:42,567 --> 00:51:44,769
CONSISTENT WITH THAT, WHAT WE

1210
00:51:44,769 --> 00:51:48,173
SEE IS THAT THE T-CELLS IN THE

1211
00:51:48,173 --> 00:51:50,742
MICE THAT HAVE TUMORS WITH A

1212
00:51:50,742 --> 00:51:54,346
SCRAMBLE CONTROL IS DECREASE BUT

1213
00:51:54,346 --> 00:51:56,581
IF YOU PRE-BLOCK PRIMARY CILIA

1214
00:51:56,581 --> 00:51:57,916
BEFORE IMPLANTATION THAT DOES

1215
00:51:57,916 --> 00:52:01,252
NOT OCCUR. SO WHAT WE ARE SEEING

1216
00:52:01,252 --> 00:52:03,321
IN VITRO MATCHES IN VIVO

1217
00:52:03,321 --> 00:52:05,423
FINDINGS HERE THAT JUST BLOCKING

1218
00:52:05,423 --> 00:52:08,493
THE PRIMARY CILIA IS ENOUGH TO

1219
00:52:08,493 --> 00:52:09,828
ACTUALLY RESTORE T-CELL FUNCTION

1220
00:52:09,828 --> 00:52:13,064
IN THE ANIMALS BY REDUCING THAT

1221
00:52:13,064 --> 00:52:16,267
MDSC POPULATION.  SO THAT WAS IN

1222
00:52:16,267 --> 00:52:18,937
BONE MARROW. WE SEE VERY SIMILAR

1223
00:52:18,937 --> 00:52:23,274
THING IN THE SPLEEN. THAT I'M

1224
00:52:23,274 --> 00:52:25,243
NOT SHOWING HERE IS IN PATIENTS,

1225
00:52:25,243 --> 00:52:26,745
US AND OTHERS HAVE ALSO

1226
00:52:26,745 --> 00:52:28,646
PUBLISHED THAT IN A PATIENT WITH

1227
00:52:28,646 --> 00:52:31,616
ADVANCE GLIOBLASTOMAS, THE

1228
00:52:31,616 --> 00:52:33,451
THYMUS IS HYPO PLASTIC BECAUSE

1229
00:52:33,451 --> 00:52:34,686
THEY LOSE HAIR T-CELLS SO ONE OF

1230
00:52:34,686 --> 00:52:36,254
THE THINGS WE ALSO DID WAS LOOK

1231
00:52:36,254 --> 00:52:39,758
TO SEE IN THESE ANIMALS WHERE WE

1232
00:52:39,758 --> 00:52:42,260
ARE BLOCKING PRIMARY CILIA, DO

1233
00:52:42,260 --> 00:52:44,029
YOU SEE RESTORATION OF T-CELLS

1234
00:52:44,029 --> 00:52:48,967
IN THE THYMUS.  AND WE DO. SO

1235
00:52:48,967 --> 00:52:50,668
I'M GOING TO TRY TO GET THROUGH

1236
00:52:50,668 --> 00:52:51,903
THE REST OF THIS RELATIVELY

1237
00:52:51,903 --> 00:52:53,438
QUICKLY. SO THE QUESTION HERE

1238
00:52:53,438 --> 00:52:55,573
FOR US WAS WELL WHY DOES THE

1239
00:52:55,573 --> 00:52:58,443
PRIMARY CILIA HAVE THAT ROLE? SO

1240
00:52:58,443 --> 00:53:00,245
PEOPLE HAVE STUDIED THAT, WELL,

1241
00:53:00,245 --> 00:53:02,914
YOU KNOW IF YOU LOOK AT PRIMARY

1242
00:53:02,914 --> 00:53:04,783
CILIA, THERE ARE VESICALES THAT

1243
00:53:04,783 --> 00:53:06,584
BUTT OFF OF THEM. I'M SHOWING

1244
00:53:06,584 --> 00:53:08,453
YOU THAT IN THE CARTOON AND ALSO

1245
00:53:08,453 --> 00:53:12,924
IN THAT HERE IN A T E M IMAGE OF

1246
00:53:12,924 --> 00:53:13,558
LONGITUDINAL SECTION THROUGH

1247
00:53:13,558 --> 00:53:17,295
PRIMARY CILIA. SO THIS IS THE

1248
00:53:17,295 --> 00:53:22,700
XENIMO BRAIN HERE, THE EXANINE

1249
00:53:22,700 --> 00:53:24,669
MICROTHANK YOU MULE, YOU CAN SEE

1250
00:53:24,669 --> 00:53:28,306
THE ECTOSOME BUDDING OFF. SO ARE

1251
00:53:28,306 --> 00:53:31,009
THESE EXTRA CELLULAR VESICLES WE

1252
00:53:31,009 --> 00:53:33,078
THINK SO IMPORTANT FOR

1253
00:53:33,078 --> 00:53:34,212
IMMUNOSUPPRESSION IN CANCER,

1254
00:53:34,212 --> 00:53:35,880
WHERE THESE VESICLE IT IS SAME

1255
00:53:35,880 --> 00:53:37,549
THAT ARE BUDDING FROM OUR

1256
00:53:37,549 --> 00:53:40,318
PRIMARY CILIA? SO THERE ARE WAYS

1257
00:53:40,318 --> 00:53:41,886
TO STUDY THAT AND SO THIS IS

1258
00:53:41,886 --> 00:53:45,356
JUST A CARTOON, THE VESICALES

1259
00:53:45,356 --> 00:53:47,125
TYPICALLY ARE MADE OF THESE

1260
00:53:47,125 --> 00:53:49,427
TETRA SPANIN PROTEINS THAT SPAN

1261
00:53:49,427 --> 00:53:51,996
THE MEMBRANE. AND WE CAN TEST

1262
00:53:51,996 --> 00:53:55,033
FOR THOSE.  WHAT WE SEE FIRST IS

1263
00:53:55,033 --> 00:53:59,003
THAT CD 9 AND CD8 1 ARE TWO WELL

1264
00:53:59,003 --> 00:54:01,439
KNOWN TETRA SPANIN PROTEINS,

1265
00:54:01,439 --> 00:54:03,108
SPECIFIC FOR EVs WE CAN SEE

1266
00:54:03,108 --> 00:54:04,976
THAT REGARDLESS OF WHETHER WE

1267
00:54:04,976 --> 00:54:08,279
HAVE KNOCKED DOWN ANY OF THESE

1268
00:54:08,279 --> 00:54:09,514
THREE PROTEINS THAT WOULD

1269
00:54:09,514 --> 00:54:11,182
OTHERWISE MAKE PRIMARY CILIA

1270
00:54:11,182 --> 00:54:15,120
DISAPPEAR WE ARE STILL SEEING CD

1271
00:54:15,120 --> 00:54:17,989
9 AND CD8 1. MORE PROOF IS THAT

1272
00:54:17,989 --> 00:54:21,059
YOU CAN DETECT THE VESICLES BY

1273
00:54:21,059 --> 00:54:22,861
TRANSMISSION ELECTRON MICROSCOPY

1274
00:54:22,861 --> 00:54:25,296
SO THEY ARE THERE. SO WE CAN

1275
00:54:25,296 --> 00:54:26,764
THEN DO NANOPARTICLE ANALYSIS

1276
00:54:26,764 --> 00:54:28,933
WHICH I CAN'T SEEM TO GET VIDEO

1277
00:54:28,933 --> 00:54:30,034
TO PLAY BECAUSE I THINK THIS

1278
00:54:30,034 --> 00:54:33,071
THAT THE WAY THIS CURSOR IS. SO

1279
00:54:33,071 --> 00:54:36,040
BELIEVE ME, THESE LITTLE WHITE

1280
00:54:36,040 --> 00:54:38,176
DOTS ON THE SLIDE ARE THE

1281
00:54:38,176 --> 00:54:39,878
NANOPARTICLES VESICALES THAT ARE

1282
00:54:39,878 --> 00:54:42,881
100 NANOMETERS AND WHAT THIS IS

1283
00:54:42,881 --> 00:54:45,183
MEASURING IN THE GRAPHS ARE BOTH

1284
00:54:45,183 --> 00:54:47,719
THE SIZE DISTRIBUTION AND THE

1285
00:54:47,719 --> 00:54:49,654
CONCENTRATION DISTRIBUTION AND

1286
00:54:49,654 --> 00:54:52,423
TO OUR SURPRISE, BLOCKING THE

1287
00:54:52,423 --> 00:54:54,125
CILIA AFFECTED NONE OF THESE SO

1288
00:54:54,125 --> 00:54:55,493
SOMEHOW THE VESICALES ARE NOT

1289
00:54:55,493 --> 00:54:57,162
NECESSARILY THE VESICALES COMING

1290
00:54:57,162 --> 00:54:58,830
OFF THE CILIA, IF YOU MOVE THE

1291
00:54:58,830 --> 00:55:01,065
CILIA, THE VESICALES ARE STILL

1292
00:55:01,065 --> 00:55:02,300
THERE, CONCENTRATIONS DON'T

1293
00:55:02,300 --> 00:55:03,735
CHANGE AND SO WE FOUND THAT VERY

1294
00:55:03,735 --> 00:55:06,404
INTERESTING. SO WE ALREADY KNEW

1295
00:55:06,404 --> 00:55:08,773
I WENT OVER THAT PAPER THAT MAX

1296
00:55:08,773 --> 00:55:10,141
PUBLISHED, THAT SHOWED THAT WHEN

1297
00:55:10,141 --> 00:55:13,478
YOU BLOCK CILIA IL 6 GOES DOWN.

1298
00:55:13,478 --> 00:55:16,614
SO THEN WE THOUGHT WELL, IL 6

1299
00:55:16,614 --> 00:55:18,850
GOES DOWN MDSC IS DOWN AND WE

1300
00:55:18,850 --> 00:55:21,219
KNOW T-CELLS ARE COMING BACK SO

1301
00:55:21,219 --> 00:55:23,388
WHAT WE ALSO ANTICIPATED HERE

1302
00:55:23,388 --> 00:55:26,357
WAS THAT PDL 1, THE PROTEIN

1303
00:55:26,357 --> 00:55:28,159
BEING TARGETED WITH ALL THESE

1304
00:55:28,159 --> 00:55:31,029
BIG POWERFUL DRUGS LIKE ETRUDA

1305
00:55:31,029 --> 00:55:33,998
ALSO GO DOWN. SO WHAT WE FOUND

1306
00:55:33,998 --> 00:55:36,034
PARADOXICALLY IS THAT WHEN YOU

1307
00:55:36,034 --> 00:55:39,137
BLOCK THE CILIA PDL 1 LEVELS GO

1308
00:55:39,137 --> 00:55:40,705
UP. SO EVEN THOUGH THIS IS THE

1309
00:55:40,705 --> 00:55:43,474
PROTEIN THAT'S THOUGHT TO

1310
00:55:43,474 --> 00:55:45,176
MEDIATE THIS BLOCKAGE OF YOUR

1311
00:55:45,176 --> 00:55:46,711
T-CELLS AND WE CAN COMPLETELY

1312
00:55:46,711 --> 00:55:48,146
PREVENT THE BLOCKAGE OF THE

1313
00:55:48,146 --> 00:55:51,015
T-CELLS BY BLOCKING CILIA, PDL 1

1314
00:55:51,015 --> 00:55:53,585
LEVELS GO UP. SO WE CAN LOOK

1315
00:55:53,585 --> 00:55:55,253
THROUGH THIS MORE AND SAY WELL

1316
00:55:55,253 --> 00:55:59,057
IS THIS RELATED TO INTERFERON

1317
00:55:59,057 --> 00:56:01,159
GAMMA SIGNALING, I DIDN'T TALK

1318
00:56:01,159 --> 00:56:02,760
ABOUT INTERFERON GAMMA TODAY BUT

1319
00:56:02,760 --> 00:56:06,264
I DID TALK ABOUT INTERLEUKIN 6

1320
00:56:06,264 --> 00:56:07,565
SIGNALING SO INTERFERON GAMMA

1321
00:56:07,565 --> 00:56:10,335
AND INTERLEUKIN 6 WORK THROUGH

1322
00:56:10,335 --> 00:56:12,403
STAT 1 AND 3 PATHWAYS SO B WHAT

1323
00:56:12,403 --> 00:56:15,073
YOU CAN SEE IS WHEN YOU BLOCK

1324
00:56:15,073 --> 00:56:16,975
CILIA, BOTH INTERLEUKIN 6 AND

1325
00:56:16,975 --> 00:56:19,010
INTERFERON GAMMA PATHWAYS GO

1326
00:56:19,010 --> 00:56:21,112
DOWN. SO ONE THING THIS TOLD US

1327
00:56:21,112 --> 00:56:23,648
WAS THAT WELL, WE ARE SEEING

1328
00:56:23,648 --> 00:56:24,682
PROTEIN CHANGES WHEN WE BLOCK

1329
00:56:24,682 --> 00:56:26,951
THE CILIA, NOT WHAT WE PREDICTED

1330
00:56:26,951 --> 00:56:28,186
AND WE WILL TALK A LITTLE BIT

1331
00:56:28,186 --> 00:56:32,156
ABOUT THAT LATER. BUT MAYBE

1332
00:56:32,156 --> 00:56:35,560
POSSIBLE THAT WHILE THE PRIMARY

1333
00:56:35,560 --> 00:56:36,861
CILIA ARE IMPORTANT FOR

1334
00:56:36,861 --> 00:56:38,596
NECESSARILY RELEASING THE

1335
00:56:38,596 --> 00:56:40,164
VESICLES THEY MAY BE PERFORM FOR

1336
00:56:40,164 --> 00:56:42,033
ALTERING THE CONTENT OF THE

1337
00:56:42,033 --> 00:56:43,268
VESICALES WHICH THEN MIGHT

1338
00:56:43,268 --> 00:56:44,435
CHANGE WHAT HAPPENS WHEN THEY GO

1339
00:56:44,435 --> 00:56:46,771
OUT INTO THE SYSTEMIC

1340
00:56:46,771 --> 00:56:48,006
CIRCULATION. SO WHAT WE DID IS

1341
00:56:48,006 --> 00:56:51,075
BLOCKED THE PRIMARY CILIA, THEN

1342
00:56:51,075 --> 00:56:54,512
WE DID PROTEOMIC SCREEN LOOKING

1343
00:56:54,512 --> 00:56:56,180
AT THE NANOPARTICLES THEMSELVES,

1344
00:56:56,180 --> 00:56:58,416
NOT THE CELLS, BUT WHAT IS THE

1345
00:56:58,416 --> 00:57:00,885
ACTUAL CONTENT IN THE

1346
00:57:00,885 --> 00:57:02,420
NANOPARTICLES FOLLOWING THIS

1347
00:57:02,420 --> 00:57:04,155
BLOCKADE OF PRIMARY CILIA IN THE

1348
00:57:04,155 --> 00:57:05,690
CELLS FROM WHICH THEY CAME. AND

1349
00:57:05,690 --> 00:57:07,859
I THIS I WHAT SHOULD BE VERY

1350
00:57:07,859 --> 00:57:08,760
CLEAR TO ANYBODY LOOKING AT THIS

1351
00:57:08,760 --> 00:57:10,828
IS THAT THE CONTENT OF THE

1352
00:57:10,828 --> 00:57:13,164
VESICALES ARE VERY DIFFERENT.  I

1353
00:57:13,164 --> 00:57:15,033
HIGHLIGHTED HERE ICAM 1 BECAUSE

1354
00:57:15,033 --> 00:57:17,702
THAT IS A PROTEIN INTRACELLULAR

1355
00:57:17,702 --> 00:57:22,006
ADHESION MOLECULE 1 THAT'S

1356
00:57:22,006 --> 00:57:23,408
IMPLICATE IN SYSTEMIC CANCERS Z

1357
00:57:23,408 --> 00:57:26,844
A MEDIATOR OF IMMUNOSUPPRESSION.

1358
00:57:26,844 --> 00:57:28,279
SO WE SHOWED NOT ONLY SEE THAT

1359
00:57:28,279 --> 00:57:30,281
IN THE PROTEOMIC SCREEN BUT WHEN

1360
00:57:30,281 --> 00:57:33,151
WE DO A FLOW CYTOMETRIC SCREEN

1361
00:57:33,151 --> 00:57:36,587
ICAM 1 ON SURFACE OF VESSELS ARE

1362
00:57:36,587 --> 00:57:40,458
DOWN SO WE CAN CONFIRM THAT. SO

1363
00:57:40,458 --> 00:57:46,364
IN SUMMARY HERE, WE HAVE MORE

1364
00:57:46,364 --> 00:57:50,568
NUANCED VIEW NOW OF HOW

1365
00:57:50,568 --> 00:57:52,370
IMMUNOSUPPRESSION MIGHT WORK IN

1366
00:57:52,370 --> 00:57:54,238
GLIOBLASTOMA. SO FIRSTLY, IT IS

1367
00:57:54,238 --> 00:57:57,775
THE TUMOR IS CONFINED TO CENTRAL

1368
00:57:57,775 --> 00:57:59,177
NERVOUS SYSTEM. BUT IT IS ABLE

1369
00:57:59,177 --> 00:58:00,912
TO HAVE SYSTEMIC EFFECTS BECAUSE

1370
00:58:00,912 --> 00:58:03,348
IT RELEASES THE VESICALES. WHILE

1371
00:58:03,348 --> 00:58:06,984
THE VESICLES ARE NOT FROM PRIMA

1372
00:58:06,984 --> 00:58:09,220
CILIA, IT APPEARS THE SIGNALING

1373
00:58:09,220 --> 00:58:11,756
MAP IS MEDIATED THROUGH PRIMARY

1374
00:58:11,756 --> 00:58:14,225
CILIA, CLANGS THE CONTENTS OF

1375
00:58:14,225 --> 00:58:15,460
THOSE VESICLES IN A MANNER

1376
00:58:15,460 --> 00:58:19,597
DEPENDENT ON IL 6 SIGNALING, AND

1377
00:58:19,597 --> 00:58:21,199
ALLOWS FOR THAT CONTENT TO BE

1378
00:58:21,199 --> 00:58:22,967
SUCH THAT WHEN IT GETS THE BONE

1379
00:58:22,967 --> 00:58:24,869
MARROW THE SPLEEN, ET CETERA, IT

1380
00:58:24,869 --> 00:58:27,038
HAS IMMUNOSUPPRESSIVE EFFECT. 

1381
00:58:27,038 --> 00:58:29,407
AND I THINK THAT THE BIG THING

1382
00:58:29,407 --> 00:58:31,175
FROM THIS IS THAT BILLIONS OF

1383
00:58:31,175 --> 00:58:36,781
DOLLARS HAS GONE INTO CREATING

1384
00:58:36,781 --> 00:58:39,016
IMMUNE CHECK POINT INHIBITORS

1385
00:58:39,016 --> 00:58:41,619
FOR THE SOLE PURPOSE OF REDUCING

1386
00:58:41,619 --> 00:58:43,020
CANCER MEDIATED

1387
00:58:43,020 --> 00:58:45,456
IMMUNOSUPPRESSION. AND WHAT WE

1388
00:58:45,456 --> 00:58:49,861
FOUND WAS THAT IF YOU HAVE EVEN

1389
00:58:49,861 --> 00:58:52,530
INCREASE IN PDL 1 IF YOUR

1390
00:58:52,530 --> 00:58:54,632
PRIMARY CILIA ARE NOT THERE THE

1391
00:58:54,632 --> 00:58:57,235
PDL 1 SIGNALING DOESN'T WORK.

1392
00:58:57,235 --> 00:58:59,237
BUT THE COROLLARY TO THAT IS

1393
00:58:59,237 --> 00:59:02,407
BLOCKING PDL 1 BY ITSELF IN

1394
00:59:02,407 --> 00:59:04,008
CONTEXT OF GLIOBLASTOMA MIGHT

1395
00:59:04,008 --> 00:59:04,842
NOT BE SUFFICIENT BECAUSE THERE

1396
00:59:04,842 --> 00:59:07,078
IS A PARALLEL PATHWAY. THAT BOTH

1397
00:59:07,078 --> 00:59:09,647
OF WHICH NEEDS TO BE INHIBITED. 

1398
00:59:09,647 --> 00:59:13,050
SO THAT MIGHT EXPLAIN A LOT OF

1399
00:59:13,050 --> 00:59:17,388
THE UNSUCCESSFUL CLINICAL TRIALS

1400
00:59:17,388 --> 00:59:20,324
WE HAVE SEEN OF IMMUNE CHECK

1401
00:59:20,324 --> 00:59:23,161
POINT INHIBITORS IN THE CONTEXT

1402
00:59:23,161 --> 00:59:24,662
OF GLIOBLASTOMAS, THEY HAVE ALL

1403
00:59:24,662 --> 00:59:25,763
FAILED AND WE HAVE IDEAS WHY

1404
00:59:25,763 --> 00:59:29,901
THAT IS. SO AGAIN, GLIOBLASTOMA

1405
00:59:29,901 --> 00:59:32,303
IS A BAD DISEASE. I WANT

1406
00:59:32,303 --> 00:59:34,138
TRAINEES TO WALK AWAY FROM HERE

1407
00:59:34,138 --> 00:59:35,940
WITH THAT AND WE NEED LOT

1408
00:59:35,940 --> 00:59:38,342
SMARTER PEOPLE THAN ME TO BE

1409
00:59:38,342 --> 00:59:40,745
STUDYING THIS. PRIMARY CILIA ARE

1410
00:59:40,745 --> 00:59:42,213
IMPORTANT IN PATHOGENESIS OF THE

1411
00:59:42,213 --> 00:59:44,248
DISEASE, BECAUSE OF ALL

1412
00:59:44,248 --> 00:59:46,317
SIGNALING IT MEDIATES BUT ALSO

1413
00:59:46,317 --> 00:59:49,120
IN TERMS OF THE WAY IT INTERACTS

1414
00:59:49,120 --> 00:59:51,522
WITH THE IMMUNE SYSTEM. AGAIN,

1415
00:59:51,522 --> 00:59:54,959
PDL 1 IN IL 6 STAT 3 PATHWAY,

1416
00:59:54,959 --> 00:59:56,627
AND THE MEDIATION OF THOSE

1417
00:59:56,627 --> 00:59:59,564
PATHWAYS THROUGH PRIMARY CILIA

1418
00:59:59,564 --> 01:00:01,032
MIGHT BE PARALLEL AND YOU MIGHT

1419
01:00:01,032 --> 01:00:02,800
NEED A NUANCED STRATEGY TO GET

1420
01:00:02,800 --> 01:00:04,368
SOME OF THESE IMMUNE CHECK

1421
01:00:04,368 --> 01:00:06,938
POINTS TO WORK. OF COURSE THIS

1422
01:00:06,938 --> 01:00:09,440
IS A SNAP SHOT OF A LOT OF

1423
01:00:09,440 --> 01:00:10,942
THINGS, NONE WOULD BE POSSIBLE

1424
01:00:10,942 --> 01:00:13,244
WITHOUT A LOT OF PEOPLE. WE HAVE

1425
01:00:13,244 --> 01:00:14,812
LESS THAN A MINUTE BUT I WILL

1426
01:00:14,812 --> 01:00:15,746
TAKE ANY QUESTIONS OR COMMENTS

1427
01:00:15,746 --> 01:00:17,715
YOU HAVE NOW. THANKS.

1428
01:00:17,715 --> 01:00:23,588
[APPLAUSE]

1429
01:00:23,588 --> 01:00:25,823
>> REMIND TORE THE ONLINE

1430
01:00:25,823 --> 01:00:28,392
VIEWERS -- REMINDER TO THE

1431
01:00:28,392 --> 01:00:29,961
ONLINE VIEWERS ANY QUESTIONS

1432
01:00:29,961 --> 01:00:32,964
SUBMIT TO LIVE FEEDBACK BUTTON.

1433
01:00:32,964 --> 01:00:34,866
AND IF WE DON'T GET TO THEM WE

1434
01:00:34,866 --> 01:00:36,834
CAN ANSWER LATER BY EMAIL. THANK

1435
01:00:36,834 --> 01:00:38,302
YOU AGAIN TO OUR WONDERFUL

1436
01:00:38,302 --> 01:00:38,636
PRESENTERS.

1437
01:00:38,636 --> 01:00:39,937
>> THANK YOU.

1438
01:00:39,937 --> 01:00:50,114
[APPLAUSE]