>> WELCOME TO
EVERYONE TO THE SECOND DAY OF
THE WORKSHOP ON LYMPHATIC SYSTEM
IN HEALTH AND DISEASE.
YESTERDAY WE HAD A SUCCESSFUL
DAY FOCUSING ON LYMPHATIC
DEVELOPMENT FUNCTION AND SOME OF
THE DISEASE CONDITIONS AND TODAY
WE WILL CONTINUE ANOTHER
GREAT -- ANOTHER DAY OF GREAT
TALKS LINED UP FOR LYMPHATIC
DISEASES, COMMUNITIES
PERSPECTIVE AND NEW TECHNOLOGIES
IN IMAGING AND MAPPING.
LET ME REMIND YOU OUR
HOUSEKEEPING ANNOUNCEMENTS, IF
YOU'RE ONLY JOINING TODAY.
THIS WORKSHOP IS RECORDED AND
WILL BE AVAILABLE FOR EVERYONE
IN PERPETUITY IN NIH VIDEOCAST
COLLECTION.
THE LINKS FOR THE VIDEOCAST
RECORDING ALONG WITH THE
DETAILED INFORMATION OF ALL
SPEAKERS CAN BE FOUND ON THE
REGISTRATION PAGE.
ALL THESE LINKS ARE POSTED.
ALSO
IN THE CHAT AND WILL BE
AVAILABLE TO EVERYONE AFTER THE
WORKSHOP AS WELL.
THE SPEAKERS WILL PRESENT THEIR
TALKS AND THEY WILL ANSWER THE
QUESTIONS AS A PANEL AT THE END
OF EVERY SESSION, AND WHICH WILL
BE LED BY THE SESSION MODERATOR.
PLEASE SUBMIT YOUR QUESTIONS,
OUR ZOOM ATTENDEES PLEASE PUT IT
IN Q & A AND VIDEOCAST WITH THE
LIVE FEEDBACK FUNCTION, AND WE
WILL GIVE TO THE MODERATOR.
THE MODERATORS WILL BE READING
AND DIRECTING YOUR QUESTIONS TO
THE PANELISTS.
WE REQUEST OUR SPEAKERS TO RAISE
HAND, UNMUTE AND ASK THEIR
QUESTIONS LIVE.
TO START THE DAY, IT IS MY
DISTINCT PLEASURE TO INTRODUCE
DR. DAVID GOFF, DIRECTOR OF
DIVISION OF CARDIOVASCULAR
DISEASES IN NHLBI, AND DR. GOFF
WILL BE GIVING THE WELCOME
REMARKS FOR THE DAY TWO.
DR. GOFF?
>> THANK YOU, SELEN.
I WANT TO THANK EVERYONE WHO HAS
PARTICIPATED YESTERDAY AND WHO
IS PARTICIPATING TODAY IN THIS
REALLY IMPORTANT WORKSHOP.
WE KNOW THAT YOU'RE ALL VERY
BUSY AND ESPECIALLY IN THE MIDST
OF THE PANDEMIC, EVERYBODY'S GOT
A LOT OF DEMANDS ON THEIR TIMES
AND YOU CHOSE TO SPEND THIS TIME
WITH US TO SHARE WITH US YOUR
THOUGHTS ABOUT HOW WE CAN MOVE
THIS FIELD FORWARD.
AND WE GREATLY APPRECIATE THAT.
THIS IS A REALLY IMPORTANT PART
OF OUR MISSION.
YOU HEARD ABOUT THAT YESTERDAY
FROM DR. ZORINA GALIS, WHO
SHARED WITH YOU THE EXTENT TO
WHICH WE SUPPORT THIS IN THE
MISSION OF THE DIVISION OF
CARDIOVASCULAR SCIENCES AND THE
NATIONAL HEART, LUNG AND BLOOD
INSTITUTE, THE LYMPHATIC SYSTEM
IS AN IMPORTANT PART OF THE
VASCULAR SYSTEM SO IT'S REALLY
AN IMPORTANT PART OF OUR MISSION
IN THE DIVISION OF
CARDIOVASCULAR SCIENCES.
AS YOU SAW YESTERDAY IN
DR. GALIS' PRESENTATION, THE
COMMUNITY IS DOING REASONABLY
WELL WITHIN THE PEER REVIEW
PROCESS WITHIN NHLBI, WHERE THE
SUCCESS RATE IS HIGHER THAN THE
TYPICAL SUCCESS RATE FOR
APPLICATIONS IN GENERAL.
SO WE'RE VERY PLEASED TO SEE
THAT, AND YET WE KNOW WE CAN DO
MORE AND NEED TO DO MORE, AND,
THEREFORE, HOSTING THIS WORKSHOP
IN COLLABORATION WITH NIDDK, AND
WE'RE LOOKING FORWARD TO YOUR
INPUT.
I WANTED TO SHARE WITH YOU MY
EXCITEMENT ABOUT WHAT I SEE AS
POTENTIAL OUTCOMES OF THIS
WORKSHOP.
FIRST WE'LL BE LOOKING FORWARD
TO A REPORT THAT WE CAN POST ON
THE NIH WEBSITE HOPEFULLY WITHIN
THE NEXT, YOU KNOW, FOUR TO SIX
WEEKS SO WE CAN GET IT OUT IN A
TIMELY MANNER TO SHARE YOUR
THOUGHTS AND YOUR INPUT WITH THE
REST OF OF THE BIOMEDICAL RESH
COMMUNITY AT LEAST AT A SUMMARY
LEVEL, AND THEN WE ANTICIPATE
YOU MAY WANT TO WRITE A PAPER
FOR PUBLICATION IN PEER REVIEW
JOURNAL AND IF YOU DECIDE TO DO
THAT, WE'LL CERTAINLY SUPPORT
YOU IN THAT EFFORT, AND WE WOULD
AGAIN HOPE THAT WOULD GET
SUBMITTED WITHIN THE NEXT SIX
MONTHS OR SO AT THE OUTSIDE, SO
THAT, AGAIN, IT'S TIMELY
INFORMATION TO GET OUT TO THE
PEER REVIEW COMMUNITY.
WE KNOW YOU'RE VERY BUSY, SO
THAT'S A TIGHT TIMELINE, BUT IF
WE'RE GOING TO GET A REPORT OUT
FROM THIS WORKSHOP, WE'D LIKE TO
GET IT OUT IN A TIMELY MANNER,
BEFORE THE INPUT AND
PRESENTATIONS GET A LITTLE BIT
DATED.
SO WE'LL LOOK FORWARD TO
SUPPORTING YOU ON THAT IF THAT'S
SOMETHING YOU'D LIKE TO DO.
WE ALSO HOPE THAT WHEN YOU GO
HOME, YOU'LL BE ENERGIZED BY THE
INTERACTIONS.
I GUESS WE'RE HOME, BUT WHEN YOU
GO BACK TO YOUR DAY TO DAY WORK,
YOU'LL BE ENERGIZED BY THE
INTERACTIONS OVER THE PAST DAY
AND TODAY AND THAT YOU'LL SUBMIT
ADDITIONAL GREAT APPLICATIONS.
I TELL PEOPLE IT'S SIMPLE TO GET
MONEY FROM NHLBI.
WRITE A GREAT APPLICATION, GET A
GREAT SCORE, ALMOST ALL THE
MONEY WE GIVE OUT EVERY YEAR
GOES IN PEER REVIEWED
INVESTIGATOR-INITIATED RESEARCH.
I DID SAY SIMPLE.
I DIDN'T SAY EASY.
YOU KNOW, SOMETIMES WE USE THE
INPUT FROM THESE KINDS OF
WORKSHOPS TO PUT OUT SPECIFIC
FUNDING OPPORTUNITIES.
I WILL SAY WE DO MORE WORKSHOPS
THAN WE CAN POSSIBLY PUT OUT
FUNDING OPPORTUNITIES, SO WE
DON'T ALWAYS DO THAT, THOUGH.
WE SOMETIMES DO, SO BASED ON
YOUR INPUT, WE MAY PUT OUT A
FUNDING OPPORTUNITY
ANNOUNCEMENT.
REGARDLESS OF THAT, WE'LL USE
YOUR INPUT TO GUIDE WHAT WE CALL
OUR SELECT PAY PROCESS, IN WHICH
WE PUT A LITTLE BIT OF MONEY
ASIDE TO PICK UP HIGH PRIORITY
APPLICATIONS THAT ARE JUST ON
THE WRONG SIDE OF THE PAYLINE,
BUT ARE HIGHLY STRATEGIC, HIGHLY
ALIGNED WITH OUR MISSION.
SO WE WILL USE YOUR INPUT TO
HELP GUIDE THAT PROCESS AS WELL.
SO I WANT TO END WHERE I
STARTED, WITH THANKING YOU AND
THE ORGANIZERS OF THE WORKSHOP
FOR COMING TOGETHER TO HELP US
ADDRESS THIS REALLY IMPORTANT
PROBLEM.
WE'RE LOOKING FORWARD TO YOUR
INPUT AND TO LEVERAGING TO MOVE
THIS FIELD FORWARD.
AND WITH THAT, I'LL PASS THE
BATON BACK TO THE CHAIRS TO GET
US KICKED OFF TODAY.
THANKS SO MUCH.
>> THANK YOU SO MUCH, DR. GOFF.
THAT WAS A VERY INSPIRING TALK.
IT'S MY PLEASURE THIS MORNING TO
INTRODUCE DR. STANLEY ROCKSON AS
OUR NEXT KEYNOTE SPEAKER.
DR. ROCKSON DOESN'T NEED AN
INTRODUCTION, ALL OF US KNOW
HIM, BUT HE'S ALSO THE PROFESSOR
OF LYMPHATIC RESEARCH AND THE
CHIEF OF CONSULTIVE CARDIOLOGY
DIVISION AT STANFORD.
DR. ROCKSON IS A PIONEER IN
LYMPHATIC RESEARCH.
HE WAS KIND ENOUGH TO MENTOR ME
WHEN I WAS FIRST GETTING STARTED
IN THIS AREA.
HIS IMPORTANT WORK IN THE ROLE
OF INFLAMMATION AS REGULATOR OF
LYMPHEDEMA DEVELOPMENT HAS LED
TO NUMEROUS CLINICAL TRIALS AND
HAS BEEN A CATALYST FOR MANY
OTHER LABORATORIES INCLUDING
MINE.
PLEASE JOIN ME IN WELCOMING
DR. ROCKSON.
>> BABAK, THANK YOU SO MUCH.
THANK YOU TO THE ORGANIZERS,
INCLUDING YOURSELF, FOR THIS
WONDERFUL INVITATION.
I'M JUST TRYING TO SHARE MY
SCREEN HERE.
THIS IS NOT WORKING.
IT WORKED A MOMENT AGO.
I'M SO SORRY, I DON'T KNOW
WHAT'S HAPPENING.
WE JUST TESTED THIS AND NOW IT
WON'T GO TO "SHARE SCREEN."
>> I THINK ZOOM IS SOMETIMES
LIKE THE LAB, SOMETHING THAT
WORKED EVERY TIME THE LAST 10
TIMES YOU DO IT, AND IT DOESN'T
WORK INEXPLICABLY.
>> RIGHT.
LET ME START ONE MORE TIME, SEE
WHAT HAPPENS.
I'M SORRY, I DON'T KNOW WHAT THE
PROBLEM IS.
IT WON'T ALLOW ME TO --
>> ARE YOU CLICKING ON THE SHARE
SCREEN BUTTON AT THE BO M BOF
YOUR SCREEN?
>> YES, I'M SELECTING POWERPOINT
AND IT JUST SHIFTS BACK TO THE
DESKTOP.
>> DO YOU HAVE YOUR POWERPOINTS
OPEN ALREADY?
>> YES.
YES.
WE JUST TESTED IT A MOMENT AGO.
IS THAT SHARING NOW?
>> NO.
IT'S NOT.
>> OKAY.
LET ME TRY ONE MORE TIME.
MY MACHINE MAKES IT LOOK AS IF
IT IS SHARING, BUT -- THIS IS
TERRIBLE.
LET'S TRY ONE MORE TIME.
I'M SO SOOR EE.
I CAN'T MAKE THIS SHARE.
I DON'T KNOW WHAT'S HAPPENED.
>> STAN, DO YOU WANT TO LOG OFF
AND JOIN BACK ON?
WE CAN MAYBE SHOW THEM FROM
HERE?
>> WOULD YOU LIKE ME TO SHARE
THEM FOR YOU?
>> PERHAPS -- WELL, WHY DON'T I
QUICKLY LOG OFF AND SEE IF I CAN
MAKE THAT WORK.
>> OKAY.
WE CAN GO ON TO THE NEXT
SPEAKER.
>> YEAH.
WHY DON'T WE DO THAT.
>> OKAY, SARAH, ARE YOU READY?
IS SARAH TEICHMANN HERE?
>> WE MIGHT HAVE TO WAIT JUST
ONE SECOND FOR DR. ROCKSON
BECAUSE SARAH IS JOINING US.
>> JOHN, I DON'T KNOW IF WE CAN
SHARE DR. ROCKSON'S SLIDES,
BUT -- OR IF IT WOULD GET IN HIS
WAY WHEN HE'S TRYING AGAIN?
>> I OFFERED.
HE DECLINED.
>> SORRY, EVERYONE.
JUST ONE MORE MINUTE.
I'M SURE IT WILL BE WORTHWHILE
TO WAIT.
>> SELEN, IT'S DHRUV.
I THINK I'M THE NEXT SPEAKER
AFTER SARAH.
I'M READY, JUST SO YOU KNOW, IN
CASE THERE'S A DELAY.
>> THANKS, DHRUV.
>> LOOK AT DHRUV, STEPPING UP!
>> I KNOW, RIGHT?
>> HE'S STILL COMING TO THE
RESCUE.
>> TAKING A CONSULT.
>> RIGHT?
>> OKAY.
STAN, WE ARE WAITING FOR YOU.
IF YOU ARE READY TO TRY, LET'S
DO IT AGAIN.
>> I'LL KEEP MY FINGERS CROSSED
HERE.
>> HERE YOU GO.
AWESOME!
>> THANK YOU.
I'M SO SOOR EE.
SORRY.
LET ME TRY AGAIN.
THANKS AGAIN TO THE ORGANIZERS
NOW, ALSO THANK YOU FOR BEING
PATIENT AND WAITING FOR ME.
THIS IS REALLY A PRIVILEGE TO BE
ABLE TO BE A PART OF THIS VERY
GROUND BREAKING CONFERENCE.
SO I'M GOING TO TALK ABOUT A
TRIP THAT'S ALREADY BEEN, I
THINK, OVER 20 YEARS IN
DURATION, AND I ONLY HAVE 20
MINUTES SO I'LL TRY TO BREEZE
THROUGH IT BUT GIVE YOU THE
HIGHLIGHTS OF WHERE WE'VE BEEN.
AND OF COURSE THE ISSUE IS, HOW
DO WE TREAT AND POTENTIALLY
REVERSE OR EVEN POTENTIALLY
PREVENT THIS PROBLEM, WHICH IS
SOME RELATIVELY ADVANCED
MANIFESTATIONS OF LYMPHEDEMA.
SO WHAT YOU SAW IN THE PRECEDING
SLIDE IS ACTUALLY STAGE THREE
LYMPHEDEMA BY ISL CRITERIA.
AND AS YOU GO THROUGH THIS
SEQUENCE FROM SUBCLINICAL
DISEASE TO FULLY EXPRESSED
DISEASE, YOU SEE THAT WHAT WE
ARE FEATURING IS THE INCREASING
PRESENCE OF TISSUE DISTORTION
AND PATHOLOGY AS A CONSEQUENCE
OF THE CHRONIC EDEMA.
AND WHILE WE HAVE REASONABLE
APPROACHES TO CONTROL EDEMA AND
INTERSTITIAL FLUID ACCUMULATION,
BOTH DIURETICS AS WELL AS
MECHANICAL INTERVENTIONS, WE
HAVE HAD HISTORICALLY LITTLE OR
NOTHING TO DO OTHER THAN
SURGICAL REMOVAL FOR THE TISSUE
DISTORTION THAT OCCURS WITH
CHRONIC EDEMA.
SO WE GO FROM THIS STATE, CLEAR
PITTING EDEMA, HERE I'VE LEFT MY
EXAMINER FINGER IMPRESSION ON
THE SURFACE OF THE LIMB, TO AN
IDENTICAL INCREASE IN LIMB
VOLUME BUT WITHOUT ANY ABILITY
TO DISTORT THE FLUID CONTENT
BECAUSE NOW THIS HAS BECOME
PREDOMINANTLY TISSUE OVERGROWTH.
SO THE QUESTION IS, HOW DO WE
DEVELOP A DRUG TO REVERSE AND
PREVENT LYMPHEDEMA?
SO WE STARTED, OF COURSE, IN THE
ANIMAL AND AS IS OFTEN THE CASE,
WE RESORT TO OUR FRIENDS THE
MICE, BECAUSE THEY REPRESENT
THIS BEAUTIFUL THROUGHPUT
OPPORTUNITY TO EXPLORE THESE
DISEASE PROCESSES.
SO WE DEVELOPED AND MODIFIED A
MODEL OF HUMAN LYMPHEDEMA IN THE
MURINE TAIL, IN WHICH WE ALLOW
THE TAIL TO BE THE SIMULACRUM OF
THE EDEMATOUS LIMB, WE DEVELOPED
A PHOTO TECHNIQUE TO BE ABLE TO
VERY ACCURATELY MEASURE CHANGES
IN TAIL VOLUME AS WE INTERVENED
IN THIS MODEL, AND WHAT WE WERE
ABLE TO IDENTIFY AND SUPPORT IS
THE NOTION THAT MURINE
LYMPHEDEMA LOOKS VERY MUCH LIKE
ANIMAL -- LIKE HUMAN LYMPHEDEMA
UNDER THE MICROSCOPE WITH THIS
TREMENDOUS EXPANSION OF THE
DERMIS AND THE SUBDERMIS, WITH
INFLAMMATORY CELL COMPONENTS,
DILATION OF THE MICRO
LYMPHATICS, AND GENERAL
DISTORTION OF THE ANATOMY THAT
WE ALSO SEE IN THE HUMAN
SETTING.
WHAT WE'RE ABLE TO SEE IS THAT
IN THE UNTREATED STATE, WE SEE
THESE TREMENDOUS LAKES OF
MICROLYMPHATIC EXPANSION, AND
WHAT WE'VE BEEN ABLE TO SEE IN
THE TREATMENT SETTING IS THAT AS
WE REVERSE THE LYMPHEDEMA AT THE
TISSUE LEVEL, WE ACTUALLY CAN
SEE THAT THESE MICROLYMPHATICS
RETURN TO THEIR NORMAL
NON-DILATED STATE WITH
PHARMACOLOGIC INTERVENTION.
BUT TO GO BACK TO THE BEGINNING
OF THE STORY, WE TOOK THE MODEL
AND DECIDED TO COMPARE SURGICAL
SHAM MODELS WITH THOSE THAT
DEVELOPED THE DISEASE WITHOUT
TREATMENT, AND WE USED WHAT AT
THE TIME WAS CUTTING EDGE
TECHNOLOGY, NOW NOT SO MUCH, OF
WHOLE GENOME TRANSCRIPTIONAL
PROFILING THROUGH MICRO ARRAY,
AND WHAT WE WERE VERY SURPRISED
TO FIND AT THAT EARLY STAGE OF
THIS PROCESS IS THE TREMENDOUS
PREDOMINENCE OF INFLAMMATORY AND
IMMUNE MECHANISMS AS BEING A
PART OF THE EXPRESSION OF THE
DISEASE, WITH VERY LITTLE
ACTUALLY RELATED TO THE VASCULAR
PROCESSES THEMSELVES.
AND THIS, OF COURSE, HELPED US
TO IDENTIFY AND SUPPORT THE
NOTION THAT THE LYMPHATICS ARE
NOT ONLY A COMPONENT OF THE
CIRCULATION, AND OF COURSE
THEY'RE VITAL HERE, BUT THEY ARE
ALSO PART OF THE IMMUNE SYSTEM
AND THIS IS REALLY AN
IMMUNOCIRCULATORY SYSTEM, AND IT
IS VERY LIKELY THAT THE
INFLAMMATORY AND IMMUNE
COMPONENTS RELATE TO THIS ASPECT
OF LYMPHATIC FUNCTION, LEADING
US TO BELIEVE THAT CHRONIC
INFLAMMATION HAS A GREAT ROLE TO
PLAY IN THE PATHOGEN PATHOE
FULLY EXPRESSED DISEASE AND THAT
THIS MIGHT BE A REASONABLE
TARGET FOR INTERVENTION.
AS WE LOOKED COMPARE CAREFUR
MICRO ARRAY OUTPUT, WE WERE VERY
STRUCK BY THE FACT THAT 5LO
APPEARED AS A VERY PROMINENT AND
UNEXPECTED FEATURE OF THE
INFLAMMATORY RESPONSE, AND THIS
HAD NOT RECEIVED MUCH ATTENTION
UP UNTIL THAT POINT, AND WE
DECIDED TO USE IT AS ONE OF THE
TARGETS FOR OUR EMPIRICALLY
DRIVEN INTERVENTION, SO WE CHOSE
A NONSTEROIDAL ANTI-INFLAMMATORY
DRUG THAT HAS THE ABILITY TO
SIMULTANEOUSLY BLOCK THE
ACTIVATION OF BOTH 5LO AND SIGH
CROW OXYGENASE AS DO ALL THE
OTHER NSAIDs, AND WHAT WE
FOUND USING THIS AGENT IS THAT
IT HAD A FUNDAMENTALLY NO EFFECT
IN THE NORMAL SETTING BUT WHEN
WE LOOKED AT ITS APPLICATION
WHEN GIVEN SYSTEMICALLY TO THE
DISEASED ANIMALS, PLACEBO, OF
COURSE, HAD NO EFFECT, BUT THE
DRUG IN A VERY SHORT PERIOD OF
TIME NOT ONLY REVERSED THE
EDEMATOUS PRESENTATION AS WE
MEASURED IT BUT ALSO REVERTED
THE SKIN ANATOMY TO
FUNDAMENTALLY A NEAR NORMAL
APPEARANCE IN A VERY SHORT
PERIOD OF TIME.
THIS WAS EXTRAORDINARILY
ENCOURAGING TO US BECAUSE UP
UNTIL THAT POINT IT WAS BELIEVED
PATHOLOGICAL STRUCTURES OF
LYMPHEDEMA WERE THE SO-CALLED
IRREVERSIBLE FACTORS IN THE
DISEASE, AND YET HERE WE HAD
EVIDENCE THAT THERE WAS
REVERSIBILITY EVEN INCLUDING
SOME REVERSIBILITY OF THE
FIBROSIS COMPONENT RELATED TO
LYMPHEDEMA.
THIS ALLOWED US TO RELATIVELY
EARLY ON MOVE AHEAD TO LOOKING
AT THE APPLICATION OF THIS -- OF
THIS COMMERCIALLY AVAILABLE DRUG
IN HUMAN LYMPHEDEMA AND WE
DECIDED TO LOOK AT SKIN
THICKNESS BY CALIPER MEASUREMENT
AS A WAY TO TRACK SOME OF THE
CHANGES THAT WE SAW UNDER THE
MICROSCOPE IN THE MOUSE MODEL,
SO HERE YOU SEE A REPRESENTATIVE
SUBJECT IN ONE OF THESE TRIALS
STARTING WITH A DISTENDABLE SKIN
THICKNESS OF 35 MILLIMETERS,
WHICH WENT DOWN AFTER IN THIS
CASE A FOUR-MONTH EXPOSURE TO
THE DRUG DOWN TO ABOUT 3 OR
4 MILLIMETERS.
VERY CLOSE TO WHAT ONE WOULD
CONSIDER NORMAL.
SO THIS WAS QUITE ENCOURAGING,
AND WE SAW THIS AS A GENERAL
TREND IN THE TRIAL SO THAT THE
PRIMARY END POINT OF CALIPER
THICKNESS WAS MET BY THE TRIAL.
WE ALSO EE WILL BE RATED AN
EMPIRIC HISTOLOGIC SCORE TO LOOK
AT SOME OF THE ATTRIBUTES UNDER
THE MICROSCOPE AND WE FOUND THAT
THE PATIENTS ENROLLED IN THE
TRIAL ACTUALLY EXPERIENCED A
VERY SUBSTANTIAL IMPROVEMENT IN
HISTOPATHOLOGY AS WELL.
NOT SURPRISINGLY
HISTOIMMUNOCHEMISTRY TO LOOK FOR
EXPRESSION OF 5-LO AND ITS
REDUCTION WITH KETOPROFEN WAS
SUCCESSFUL.
THIS LED US BACK TO THE ANIMAL
MODEL BECAUSE NOW WE WERE VERY
INTERESTED TO KNOW IS THIS
CYCLOOXYGENASE CAUSING
IMPROVEMENT, 5-LO INHIBITION OR
SOME COMBINATION OF THE TWO?
AT THIS POINT I HAD THE
SERENDIPITY TO WORK WITH ONE OF
MY COLLEAGUES FROM STANFORD, DRE
HEARING FROM HIM SHORTLY AND I
HOPE HE WILL FILL IN SOME OF THE
DETAIL I DON'T HAVE TIME TO TALK
ABOUT, BUT WHAT WE DETERMINED IN
OUR SUBSEQUENT WORK AS WE TRIED
TO LOOK AT THE 5-LO PATHWAY IS
THAT IN FACT IT IS THE 5-LO
PATHWAY THAT SEEMS TO BE THE
AGENT OF INTEREST IN THE
TREATMENT RESPONSE, AND WHAT WE
WERE ABLE TO SHOW IS THAT WHEN
WE SPECIFICALLY BLOCKED A
DOWNSTREAM MEDIATOR FROM 5-LO
ACTIVATION WHICH IS CALLED LTB4,
WE FOUND THAT WE COULD REVERT
WHAT AMOUNTS TO A MOUSE TAIL
LYMPHOSCINTOGRAM FROM ITS NORMAL
PATTERN BACK TO A NEARLY NORMAL
PATTERN WITH JUST AS LITTLE AS
ONE WEEK OF EXPOSURE TO A
SYSTEMIC ANTAGONIST OF THE
ENZYMATIC PROCESS SO THIS IS
UNTREATED LYMPHEDEMA WITH HUGE
LAKES OF INTERSTITIAL FLUID
EQUIVALENT TO THE DERMAL BACK
FLOW WE SEE BACK TO A NEARLY
NORMAL PATTERN.
JUST TO SHOW YOU THAT THIS IS
NOT JUST A MICROVASCULAR
PHENOMENON, IN COLLABORATION
WITH DR. BRANDON DIXON, WE
ACTUALLY PERFORMED ICG
LYMPHOGRAPHY AND WHAT YOU SEE
PRIOR TO THE SITE OF SURGICAL
ABLATION, YOU WILL SEE RETURN OF
FLOW THROUGH THE MAJOR
COLLECTING VESSEL THAT LEADS
BACK TO THE ANIMAL.
I WON'T TAKE THE TIME TO SHOW
YOU THE SALINE CONTROL, EXCEPT
TO SAY THAT IN FACT WE SEE NO
SIMILAR VISUALIZATION.
SO WHAT WE LEARNED FROM THIS
ANALYSIS IS THAT HOW YOU BLOCK
INFLAMMATION HAS A TREMENDOUS
IMPACT ON WHETHER OR NOT YOU CAN
IMPROVE THE MICRO HISTOLOGY AND
THE FUNCTION IN THE DISEASED
ANIMAL.
SO WHAT WE LEARNED IN GENERAL IS
THAT 5-LO OR ANY OF THE AGENTS
THAT COULD BLOCK LTB4 EXPRESSION
WERE SUCCESSFUL IN IMPROVING
TAIL VOLUME AND ALL THE OTHER
ATTRIBUTES OF DISEASE BUT ALL
THE OTHER PATHWAYS WERE NEGATIVE
INCLUDING DIRECT INHIBITION OF
CYCLOOXYGENASE.
WE ALSO SAMPLED LTB4 IN THE
SERUM OF THE MICE AND WE DID A
SIMILAR ANALYSIS IN LYMPHEDEMA
HUMAN SUBJECTS COMPARING THEM TO
HEALTHY CONTROLS, AND IN BOTH
CASES, THERE IS DRAMATIC
INCREASE IN THE DETECTABLE
CONCENTRATIONS OF THIS
INFLAMMATORY MEDIATOR WITHIN THE
SERUM.
SO THIS LED US TO BELIEVE, AND
WE CONTINUE TO BELIEVE THAT, IN
FACT, LTB4 IS THE AGENT THAT IS
DRIVING THE PROGRESSION FROM
LYMPHEDEMA TO THE PATHOLOGY AT
THE TISSUE LEVEL.
LTB4 IS A VERY POTENT AGENT, I
DON'T HAVE TIME TO TALK ABOUT IT
IN DETAIL HERE, BUT WE CONTINUE
TO BE VERY INTERESTED IN IT.
WE NEXT WENT ON TO LAUNCH A
PLACEBO CONTROL TRIAL LOOKING AT
LYMPHEDEMA IN THE LEG IN BOTH
PRIMARY AND SECONDARY
LYMPHEDEMA, IN WHICH WE USED THE
SAME LTB4 ANTAGONIST THAT WAS
USED IN THE MURINE STUDIES.
THIS AGENT, UBENIMEX IS AN AMINO
PEPTIDASE THAT HAS THE ABILITY
TO BLOCK A VARIETY OF PROTEIN
ACTIONS INCLUDING THE ENZYME OF
INTEREST THAT WE WERE LOOKING
AT.
UNFORTUNATELY, I CONTINUE TO GET
ASKED THIS QUESTION ON A
WEEK-BY-WEEK BASIS, WE DID HAVE
TO TERMINATE THE STUDY FOR
FUNDING REASONS BEFORE WE
REACHED THE ENROLLMENT THAT WAS
PREDICTED BY SAMPLE SIZE
CALCULATION, WE NEEDED TO STUDY
250 SUBJECTS, WE GOT TO STUDY
ONLY 50, SO WE REALLY ARE NOT
ABLE TO ANALYZE THE PRIMARY END
POINT, BUT JUST TO TANTALIZE YOU
INTO WHAT WE SAW IN SOME OF THE
EXPERIMENTAL AGENT RECIPIENTS,
HERE IS ONE OF THE LAST PATIENTS
WE ENROLLED IN THE STUDY, WHO
HAD VERY ADVANCED LYMPHEDEMA OF
A SINGLE LIMB BASED ON CANCER
THERAPEUTICS, AND YOU CAN SEE
WHAT HER LEG LOOKED LIKE PRIOR
TO ENROLLMENT IN THE STUDY.
SHE RECEIVED THE DRUG IN A
DOUBLE BLIND FASHION FOR SIX
MONTHS, LATER UNBLINDED, AND SHE
SENT ME THE PHOTOGRAPH ON THE
RIGHT 18 MONTHS AFTER SHE
STOPPED THE DRUG, AND YOU CAN
SEE THE PERSISTENT AND VERY
DRAMATIC IMPROVEMENT IN THE
APPEARANCE OF HER LIMB BASED
UPON THE EXPOSURE TO THE DRUG
AND NO OTHER SPECIFIC
INTERVENTION.
SO LET ME TELL YOU BRIEFLY ABOUT
THE NEXT ITERATION OF THIS
JOURNEY WHICH WE HAVE JUST
LAUNCHED AND WE HOPE WILL LEAD
US TO THE DEFINITIVE TRIAL.
WE ARE NOW LOOKING AT A MUCH
MORE SPECIFIC ANTAGONIST OF LTBD
ACEBILUSTAT.
HERE YOU SEE THE MOLECULE
DEPICTED.
IT'S AN ORALLY BIOAVAILABLE
SMALL MOLECULE AND IT HAS THE
ABILITY TO BLOCK LEUKOTRIENE
A4 HYDROLASE, THE ENZYME THAT
PRODUCES LTB4, A POTENTIAL
ANTI-INFLAMMATORY AGENT THAT
SPECIFICALLY TARGETS THIS
ENZYME.
IT INHIBITS THE PRODUCTION OF
LTB4 AND THEN WE HOPE THAT IT
WILL HAVE THE INTENDED EFFECT IN
HUMAN LYMPHEDEMA.
AS THOSE OF YOU WHO CONDUCT
CLINICAL TRIALS ALREADY KNOW,
IT'S A COMPLICATED PROCESS.
WE'VE BEEN WORKING WITH THE FDA
AND OTHER REGULATORY AGENCIES
OVER THE LAST 24 MONTHS AND WE
HAVE JUST LAUNCHED THE TRIAL A
COUPLE OF MONTHS AGO AFTER A LOT
OF PREPARATORY WORK.
I'M FORTUNATE TO HAVE THE
SUPPORT OF AN INTERNAL
ORGANIZATION AT STANFORD CALLED
THE INNOVATIVE MEDICINE'S
ACCELERATOR AND RECEIVED
GRANTING THROUGH A COMPETITIVE
PROCESS AND ALSO HAVE RECEIVED
FUNDING FROM THE PHARMACEUTICAL
SPONSOR WHO HOLDS THE RIGHTS TO
THE DRUG CALLED CELLTAXIS.
TO BRIEFLY LET YOU KNOW WHAT
WE'RE DOING, WE'RE LOOKING AT
THIS POINT AT ARM LYMPHEDEMA IN
A SINGLE LIMB PER SUBJECT IN
ORDER TO ACHIEVE AS MUCH
HOMOGENEITY IN THE PATIENT
POPULATION AS POSSIBLE.
I FEEL THAT ARM LYMPHEDEMA HAS
MUCH MORE HOMO JE HOMOGENEIS
COUNTER PART IN THE LEG, GREATER
THAN SIX MONTHS DURATION, THIS
CAN BE MALES OR FEMALES WHO ARE
ADULTS.
THIS IS MEANT TO BE AN OPEN
LABEL OBSERVATION OF THE
ACTIVITY OF THE DRUG.
IN THIS CASE, WE HAVE DECIDED TO
CONTINUE TO LOOK AT DERMAL
ULTRASOUND BY ULTRA SONOGRAPHY
ALTHOUGH WE WILL CONTINUE TO
MEASURE BY CALIPER AS WELL AND
WE WILL HAVE A QUALITY OF
SECONDARY END POINTS INCLUDING
QUALITY OF LIFE AND OARL
MEASURES OF THE DISEASE.
ALL PARTICIPANTS DO RECEIVE
ACTIVE DRUGS.
THEY ARE GOING TO BE FOLLOWED
OVER A NINE MONTH PERIOD OF TIME
AT THREE-MONTH INTERVALS IN A
SINGLE CENTER STUDY HERE AT
STANFORD.
IT IS A NONINVASIVE STUDY, AND
AS I'VE SAID, WE'LL BE MEASURING
DERMAL THICKNESS, BOTH BY
ULTRASOUND AND BY CALIPERS, AND
WE'LL BE DOING MOLECULAR
ANALYSIS AS WELL AS ROUTINE
CHEMICAL ANALYSIS TO LOOK FOR
ANY POTENTIAL FOR TOXICITY.
I'VE ALREADY MENTIONED THE
DURATION OF GREATER THAN SIX
MONTHS.
WE WILL WORK WITH PATIENTS WHO
HAVE HAD PRIOR MICROVASCULAR
INTERVENTIONS PROVIDED THAT
THEY'VE HAD AT LEAST ONE YEAR
SINCE THEIR SURGICAL
INTERVENTION, AND THAT THEY
CONTINUE TO HAVE SUITABLE
MEASURABLE MANIFESTATIONS OF THE
DISEASE.
WE WILL CONTINUE ALL USUAL
INTERVENTIONS FOR THE
LYMPHEDEMA, ALL THE PHYSICAL
INTERVENTIONS, AND WITHOUT
ADDITION OF ANY MAINTENANCE
MODALITIES DURING THE NINE
MONTHS OF OBSERVATION, AND WE
WILL NOT BE ABLE TO DEAL WITH
PATIENTS WHO WILL HAVE SURGICAL
INTERVENTION, OF COURSE, DURING
THE STUDY.
AND WE WILL EXCLUDE ANY OTHER
MEDICAL CONDITIONS THAT PRODUCE
LYMPHEDEMA.
SO WITH THAT, I HOPE TO COME
BACK AT SOME POINT IN THE NEAR
FUTURE AND TELL YOU THAT WE
INDEED SUCCEEDED AND WE CAN GO
ON TO A FULL PLACEBO CONTROLLED
TRIAL.
I WANT TO ACKNOWLEDGE MY SOURCES
OF FUNDING.
I WANT TO ACKNOWLEDGE ALL OF MY
INCREDIBLE COLLABORATORS OVER
THE YEARS, INCLUDING DR. NICOLLS
AND DR. ME MEHRARA.
SOME OF THEM ARE STILL AROUND
AND WITH ME.
I ALSO WANT TO ESPECIALLY
ACKNOWLEDGE ONE SCIENTIST WHO
WORKED WITH US IN AN
EXTRAORDINARY FASHION ON THE
MURINE STUDIES RELATED TO LTB4.
AMY IS A PHENOMENAL SCIENTIST
AND I'M PROUD TO SAY THAT THIS
WORK WON HER AN AWARD AT THE
FIRST ITERATION OF THE LYMPHATIC
FORUM CONFERENCE.
HERE SHE IS IN FRONT OF HER
POSTER.
SO JUST TO SUMMARIZE THE
QUESTIONS THAT REMAIN, OF
COURSE, WILL THE DRUG WORK, IS
THERE A ROLE FOR PHARMACOLOGY
AND LYMPHEDEMA PREVENTION?
DO WE HAVE A ROLE FOR THIS
SIMILAR PATHWAY IN OTHER
ITERATIONS OF LYMPHATIC DISEASE,
INCLUDING VASCULAR
MALFORMATIONS, LIPEDEMA AND
OTHERS?
HOW DOES LEUKOTREEN ACTIVATION
RELATE TO -- WHICH OF COURSE
WILL PROBABLY BE A SLOWER
RESPONSE PROCESS, AND HOW DOES
LEUKOTRIENE ACTIVATION RELATE TO
DOWNSTREAM CYTOKINE ACTIVATION
AND ARE THERE OTHER TARGETED
OPPORTUNITIES?
SO IN SUMMARY, I WANT TO BELIEVE
THAT ANYTHING IS POSSIBLE.
IT'S STILL HARD FOR ME TO
BELIEVE THAT WE'VE COME THIS
FAR, BUT WE'RE NOT DONE YET AND
WE HOPE THERE WILL BE GREATER
SUCCESSES IN THE FUTURE.
SO THANKS VERY MUCH FOR THE
OPPORTUNITY TO SPEAK TO YOU THIS
MORNING.
>> THANK YOU, DR. ROCKSON.
THAT WAS FANTASTIC.
I THINK IN THE INTEREST OF TIME,
WE'RE GOING TO TAKE QUESTIONS
FROM DR. ROCKSON AT THE END OF
SESSION FIVE AND INCLUDE THAT IN
THERE, IF THAT'S OKAY WITH YOU.
>> YES, THANKS SO MUCH.
>> GREAT.
THANK YOU SO MUCH, STAN.
THAT WAS REALLY LOVELY.
WE'LL KEEP OUR FINGERS CROSSED
FOR THE CLINICAL TRIAL.
SO NOW IT'S MY PLEASURE AND
DELIGHT TO INTRODUCE DR. SARAH
TEICHMANN, THE CO-FOUNDER AND
PRINCIPAL LEADER OF THE HUMAN
CELL ATLAS, INTERNATIONAL
CONSORTIUM AND HEAD OF CELLULAR
GENETICS AT THE WELLCOME SANGER
INSTITUTE.
THE TITLE OF HER SPECIAL
INTEREST TALK IS "MAPPING THE
HUMAN BODY ONE CELL AT A TIME."
AND I KNOW THE LYMPHATIC FIELD
WILL BENEFIT FROM HER EXPERTISE
IN DEFINING CELLS AND SINGLE
CELL RESOLUTION IN DIVERSE
ORGANS, INCLUDING LYMPHOID
ORGANS.
SO SARAH, IF YOU CAN SHARE YOUR
SCREEN, THERE YOU GO.
IT'S ALL YOURS.
THANK YOU, SARAH.
>> THANK YOU, ANDREA, FOR THAT
KIND INTRODUCTION.
I HOPE YOU CAN SEE THIS AND HEAR
ME WELL.
FANTASTIC.
AS ANDREA SAID, THE APPROACH
THAT WE'VE BEEN TAKING IN THE
HUMAN CELL IN THIS COMMUNITY IS
MAPPING THE CELLS IN THE HUMAN
BODY.
AND THE IDEA HERE GOES BACK OVER
20 YEARS, AND WHAT I'M CITING
HERE IS FROM SYDNEY BRENNER
WHERE HE SAYS WE NEED A PROGRAM
OF MAKING MAPS OF CELLS AND MAPS
OF HOW CELLS TALK TO EACH OTHER.
THE CELLMAP PROJECT FOR WHICH WE
DON'T NEED A MODEL ORGANISM, IN
OTHER WORDS WE CAN JUST STUDY
THE HUMAN BODY AS OPPOSED TO
MOUSE, FISH, SO ON, WILL BE ONE
OF THE THINGS TO OCCUPY US FOR
THE NEXT FEW DECADES.
SO THIS IDEA WE NEED TO
UNDERSTAND THE MOLECULAR AND
CELLULAR BASIS OF THE HUMAN
BODY, YOU KNOW, IS IMPORTANT
CLEARLY FOR BIOMEDICAL RESEARCH
AND SORT OF CAME TO FRUITION,
REALLY, WITH TECHNOLOGIES THAT
HAVE ADVANCED OUR ABILITY TO
STUDY CELLS IN A QUANTITATIVE
WAY.
AND IT WAS THAT, THE SINGLE CELL
GENOMICS AND SPATIAL GENOMICS
TECHNOLOGIES THAT GAVE THE --
REALLY BUOYED THE IDEA OF AN
INTERNATIONAL HUMAN CELLS
CONSORTIUM.
THE MISSION OF THIS
INTERNATIONAL PROJECT IS TO
CREATE A COMPREHENSIVE REFERENCE
MAP OF OUR CELLS AND THAT'S BOTH
FROM THE POINT OF VIEW OF
CURIOSITY-DRIVEN BASIC SCIENCE
AS WELL AS APPLICATIONS TO
DIAGNOSTICS AND TREATS DISEASE.
JUST TO SET THE XENO, SCENE,E
LIVED THROUGH A REVOLUTION IN
GENOMICS WHERE WE'RE ABLE TO
SEQUENCE THE NUCLEIC CONTENTS OF
INDIVIDUAL KELS CELLS, AND,
THEREFORE, DESCRIBE THE CELL
TYPES AND CELL STATES IN A
TISSUE SAMPLE.
I HAVE A SAMPLE OF THE HEART
HERE, IN TERMS OF THE GENOMIC
CONTENT OF THE CELLS OR THEIR
NUCLEON.
THEIR MOST COMMON MODALITY
MEASURE IS RNA, REFLECTING THE
GENES THAT ARE EXPRESSED IN
CELLS' NUCLEI AND AMPLIFIED BY
TRANSCRIPTION.
WHAT THIS ALLOWS US TO DO IS
THEN ANALYZE THAT HIGH
DIMENSIONAL DATA AND EXPRESS
GENES AS A MATRIX AND DEFINE
INDIVIDUAL CELL STATES WHICH ARE
KIND OF REFLECTED IN THIS
TWO-DIMENSIONAL SPACE BY USING
COMPUTATIONAL METHODS.
THE SINGLE CELL OR SINGLE
NUCLEAR TECHNOLOGIES HAVE KIND
OF ADVANCED A PACE AND IN
PARALLEL, WE'VE HAD SPATIAL
GENOMICS, SPATIAL
TRANSCRIPTOMICS TECHNOLOGIES
RUNNING FOR US AT THE SAME TIME
AND THERE ARE DIFFERENT
APPROACHES HERE.
SEQUENCING-BASED APPROACHES TO
SORT OF MAP THE GEOGRAPHY OF THE
TRANSCRIPTOME OF THE TISSUE
SECTION AND THEN IMAGING-BASED,
WHICH IS HIGH DIMENSIONAL
MICROSCOPY OF RNA OR OF PROTEIN
AND, OF COURSE -- WHO INTRODUCED
ME IS ONE OF THE DEVELOPERS
OF -- PROTEIN IMAGING.
I WON'T TALK ABOUT THIS SO MUCH
IN MY TALK.
WHAT I WANT TO FOCUS ON IS
ONGOING PROJECT IN MY LAB, WHICH
IS UNPUBLISHED AND I'M SHARING
THIS WITH YOU HERE IN A SORT OF
UNFINISHED STATE, WHERE WE ARE
BASICALLY TAKING TOGETHER
PUBLISHED DATASETS FROM THE
COMMUNITY INCLUDING MY OWN GROUP
AND SOME UNPUBLISHED DATA TO
CREATE OR TO SORT OF ASSEMBLE AN
OVERVIEW OF THE VASCULATURE IN
OUR BODY, AND THAT INCLUDES THE
BLOOD VESSELS AND THE LYMPHATIC
VESSELS AND THEN RELATE THE
DIFFERENT CELL STATES TO DISEASE
ASSOCIATIONS AND SO ON.
I JUST WANT TO GIVE YOU A
FEELING FOR HOW THE HUMAN CELL
IN THIS DATA CAN START
CONTRIBUTING TO THE
UNDERSTANDING OF OUR
VASCULATURE.
AND I THINK THIS IS A REALLY
EXCITING JUNCTURE IN THE PROJECT
BECAUSE WE'VE NOW, AS A
COMMUNITY, YOU KNOW, ACROSS THE
WORLD GENERATED ENOUGH DATA THAT
WE'RE SORT OF AT THE POINT WHERE
WE CAN START ASSEMBLING A DRAFT
OF THE HUMAN -- A FIRST DRAFT OF
THE CELLS IN THE HUMAN BODY, AND
START TAKING A STEP BACK AND
LOOKING ACROSS THE DIFFERENT
ORGANS AND TISSUES AND GET AN
OVERVIEW OF DISTRIBUTED SYSTEMS
LIKE THE VASCULATURE SYSTEM AND
SO ON.
SO IN THE NEXT FEW MINUTES, I'LL
FOCUS ON WORK BY A POSTDOC IN
THE GROUP WORKING TOGETHER WITH
OTHERS WHERE WE'RE STARTING TO
DIG INTO THIS DATA AND MINE IT
AND START TO SEE WHAT WE CAN
LEARN FROM IT.
STATING WHAT'S PROBABLY OBVIOUS
TO EVERYONE IN THE AUDIENCE IS
IN BLOOD VESSELS WE'VE GOT
ENDOTHELIAL CELLS, WHICH ARE
ALSO CONSTITUENTS OF LYMPHATIC
VESSELS, AND THEN IN BLOOD
VESSELS, WE'VE GOT SMOOTH MUSCLE
CELLS AND PARASITES AS WELL.
AND FOR THE BLOOD VESSELS, WE'VE
GOT ARTERIES AND ARTERIOLES,
CAPILLARY, VEINS AND VENULES,
WHEREAS WITH LYMPHATICS, THE
MAJOR DIFFERENCES ARE REALLY THE
VESSELS WITHIN LYMPH NODES AND
AS COMPARED TO SORT OF
DISTRIBUTED IN PERIPHERAL
TISSUES.
IN A RECENT REVIEW BASICALLY
THERE'S THIS FIGURE SHOWING THE
ENDOTHELIAL CELLS THAT ARE KIND
OF LINING THE INSIDE OF THE
VESSEL AND THEN YOU'VE GOT
THICKER WALLS OF SMOOTH MUSCLE
CELLS AROUND ARTERIES VERSUS
VEINS, OF COURSE, AND THEN THE
SMALLEST OF THE CAPILLARIES,
WHICH AT BEST HAVE SORT OF
PARASITES AROUND THE ENDOTHELIAL
CELLS.
SO THE APPROACH WE'RE TAKING
HERE IS ASSEMBLING DATA FROM
INDIVIDUAL PUBLICATIONS THAT
ENCOMPASS ALL OF THE TISSUES
THAT YOU CAN SEE HERE, WHERE --
OR IN COLLABORATION WITH OTHER
GROUPS OR INDEPENDENT GROUPS
HAVE STUDIED DIFFERENT TISSUES
IN DEPTH, AND THEN ALSO SORT OF
LARGE CROSS -- ALSO RECENT BRAIN
PUBLICATION AND WHAT THEY DID
WAS ASSEMBLE THIS INTO OVER A
MILLION CELLS AND THEN PROCESSED
THE DATA IN A UNIFORM WAY TO
ACCOUNT FOR DONOR VARIATION,
DIFFERENT NOISE SUBTRACTION
APPROACHES AND SO ON, IN ORDER
TO END UP WITH ABOUT 900,000
CELLS AFTER QUALITY CONTROL, AND
SHE THEN COMPUTATIONALLY, USING
CELL
CELLTYPIST, PREDICTED ACROSS
THIS DATASET AND SEG MEANTED OUT
THE VASCULAR CELLS THAT YOU CAN
SEE AT THE TOP HERE,
ENDOTHELIAL, ENDO, MURAL,
DIFFERENT SMOOTH MUSCLE TYPES
AND SO ON AND EXCLUDED THE
EPITHELIAL, ET CETERA, CELLS.
SO WHAT WE'RE LEFT WITH, THEN,
IS 120,000 CELLS.
OR NUCLEI.
AND THESE BELONG TO 17
ENDOTHELIAL CELL SUBTYPES, EIGHT
MURAL CELL SUBTYPES, SO SMOOTH
MUSCLE AND PARASITES SURROUNDING
THE PACKAGING AROUND THE
ENDOTHELIAL CELLS, AND THEN UP
HERE, YOU CAN SEE LYMPHATIC
ENDOTHELIAL CELLS AND DOWN HERE
A SORT OF SPECIAL SUBSET THAT WE
ANNOTATED AS LITTORAL CELLS.
THIS IS AN INTERESTING SPECIAL
TIED OF ENDOTHELIAL CELL WE SEE
HERE FOR THE FIRST TIME IN HUMAN
TISSUES AT SINGLE CELL
RESOLUTION THAT ARE LINING THE
VENOUS SINUSES AT THE RED PULP.
FOR THESE CELLS AS FOR ALL OF
THE SINGLE CELL DATASETS, THE
COOL AND VERY POWERFUL THING IS
THAT YOU'RE ABLE TO DEFINE
ESSENTIALLY THE GENES THAT ARE
ACTIVE IN EACH CELL AND NUCLEUS.
SO YOU'RE ABLE TO PREDICT THE
ACTIVE SET OF PROTEINS THAT MAKE
UP THE CELL AND DEFINE THE
MOLECULAR MARKERS.
SO FOR THESE SPECIAL CELLS IN
THE SPLEEN, WE CAN -- SPECIAL
ENDOTHELIAL CELLS, THEY HAVE --
PARASITES, SMOOTH MUSCLE CELLS
AND SO ON IN THE OTHER VESSELS,
THE OTHER CELLS.
THEY HAVE CHEMOKINE RECEPTOR
UNIQUE PROFILE, APOC1 AND SO ON.
THE POINT I'M TRYING TO RATE ISS
THE CELL-SPECIFIC MOLECULES THAT
CONSTITUTE THAT CELL TYPE OR
CELL STATE OR CELL POPULATION.
SO IT ALLOWS YOU TO BASICALLY
INTERPRET THE CHARACTERISTICS OR
FUNCTIONAL FEATURES OF THE CELL
POPULATION.
IN -- MOVING ON TO OTHER
ENDOTHELIAL CELLS, THAT WAS A
DESCRIPTION OF THIS CLUSTER THAT
YOU COULD SEE WAS KIND OF AN
OUTLIER VERSUS THE OTHER BLOOD
VESSEL ENDOTHELIAL CELLS KIND OF
IN TERMS OF HAVING A VERY
DISTINCT MOLECULAR FINGERPRINT
BECAUSE OF THE SPECIAL ROLE OF
THESE CELLS IN THE SPLEEN, WE
CAN SURVEY THE OTHER ENDOTHELIAL
CELL TYPES AND IN THE REST OFE
TISSUES IN THE HUMAN BODY THAT I
SHOWED YOU AND DEFINE THESE 17
SUBSETS THAT I MENTIONED.
THE EXCITE THING IS WHEN YOU
INTEGRATE ALL OF THAT DATA,
MEANING YOU OR SORT OF START
PULLING OUT SORT OF SPECIFIC
SUBSETS THAT HAVEN'T BEEN
NOTICED BEFORE IN TERMS OF WHEN
EACH OF THE DATASETS IS
CONSIDERED INDIVIDUALLY, SO THE
SUM OF THE PART IS GREATER THAN
THE WHOLE FROM A DATA MINING,
DATA ANALYSIS POINT OF VIEW.
HERE WHAT YOU CAN SEE IS THAT
THERE ARE VEINS AND VENULAR
CELLS ACROSS THE TOP HERE IN
THIS SORT OF BLUE SHADES,
ARTERIES, AND ARTERIAL CELLS IN
SORT OF PINKISH SHADES ON THE
RIGHT-HAND SIDE, AND THEN ALL
THE CAPILLARIES IN THE DIFFERENT
SHADES ALONG THE LEFT-HAND SIDE
HERE, AND WITHIN THESE 17
DIFFERENT ENDOTHELIAL CELL
STATES.
AND KIND OF SORT OF FITTINGLY
ACROSS THE CENTER OF THIS
TWO-DIMENSIONAL PROJECTION OF
CELL TYPES AND CELL STATES ARE
ENDOTHELIAL CELLS THAT ARE
SHARED ACROSS ALL ORGANS, THAT
INCLUDES ACTIVATED VENOUS
ENDOTHELIAL CELL TYPE, VENULAR
AND VENOUS ENDOTHELIAL CELLS AS
WELL AS -- KIND OF SPRINKLED
AROUND THE EDGES AND THESE
BELONG TO THE SORT OF CAPILLARY
CELL TYPES SPECIFIC TO MUSCLE
CELL TYPES, CARDIAC AND -- THIS
IS INDICATING CAPILLARIES THAT
ARE TAKEN FROM BETWEEN THE RIBS
BASICALLY, FAT CAPE CAPILLARN
FAT TISSUE, THEY HAVE SPECIFIC
SORT OF CHARACTERISTICS THAT ARE
DIFFERENT, AND THEN WE'VE GOT
AORTIC ENDOTHELIAL CELLS, END
CARD YAL ENDOTHELIAL CELLS, THAT
HAVE CHARACTERISTICS THAT ARE
DISTINCT FROM THE SORT OF SHARED
CANONICAL ARTERIOLE --
ENDOTHELIAL AND CAPE LARRY CELL
STATES, SO THERE'S A CORE OF
ENDOTHELIAL CELL TYPES THAT ARE
SHARED ACROSS TISSUES BUT THEN
THERE ARE ALSO TISSUE-SPECIFIC
SORT OF SPECIALIZED CELL STATES
THAT WE CAN DEFINE IN THAT
UNBIASED GENOMIC APPROACH.
IN TERMS OF ARTERIAL CELL TYPES,
BASICALLY, WHAT WAS INTERESTING
IS THAT THERE ARE TWO MAIN KIND
OF CANONICAL ARTERIAL CELL TYPES
THAT I SHOWED YOU HERE THAT ARE
SHARED ACROSS ALL ORGANS THAT
ARE ARTERIAL AND ARTERIOLAR.
BASICALLY THE SORT OF MOLECULAR
FINGERPRINT IS DIFFERENT BETWEEN
THE TWO, WHERE THE
SULF1 POSITIVE ARTERIAL CELLS
ARE KIND OF ENRICHED IN THE
ARTERIES VERSUS THE ARTERIOLES,
THE SMALLER VESSELS.
AND IT'S NOT THAT -- SO THIS IS
SHOWING THE PREDICTION FROM THE
GENOMICS VALIDATED IN MICROSCOPY
STAINING OF THE SULF1, SEMA3 --
IN THE GUT IN THIS CASE, AND
WHAT WE CAN SEE HERE IS THAT THE
BIGGER OF THE ARTERY IS, THE R
FRACTION OF THIS ENDOTHELIAL
CELL POPULATION THERE IS, AND WE
THINK THIS IS BECAUSE BASICALLY
THIS AR HAS MORE EXTRACELLULAR
MATRIX COMPONENTS, MORE
MOLECULES THAT ARE LINKED TO
ESSENTIALLY STIFFNESS BUT ALSO
REGULATION OF SMOOTH MUSCLE, AND
THE ARTERIOLAR ENDOTHELIAL CELLS
HAVE MORE MOLECULES ASSOCIATED
WITH REGULATION OF
ANGIOGENESIS -- DEVELOPMENT AND
SO ON.
SO THIS KIND OF SHOWS YOU THE
SORT OF PARADIGM FOR HOW WE CAN
BASICALLY MINE THE DATA FROM THE
GENOMICS POINT OF VIEW,
INTERPRET IT, AND THEN GO INTO
THE TISSUE SECTION, STAIN AND
ANALYZE MY MICROSCOPY AND STAT
UNDERSTANDING HOW THESE BUILDING
BLOCKS ACTUALLY MAKE VESSELS OF
DIFFERENT SIZES.
AND OVER HERE IS JUST AN
ILLUSTRATION OF A SPECIFIC --
TISSUE-SPECIFIC, ORGAN-SPECIFIC
ENDOTHELIAL POPULATIONS
INCLUDING THE AORTIC ENDOTHELIAL
CELLS AND PULMONARY -- THAT HAVE
THESE SPECIFIC MOLECULAR
CHARACTERISTICS THAT YOU CAN SEE
ALONG THE BOTTOM.
I WON'T GO INTO TOO MUCH DETAIL
HERE.
THEN SORT OF MOVING ON TO THE
CAPILLARIES, WHICH, OF COURSE,
AREN'T SURROUNDED BY SMOOTH
MUSCLE BUT INSTEAD BY PARASITES,
WHAT WE CAN -- WE CAN
DISTINGUISH, AGAIN, THE
FINGERPRINT OF THE CAPILLARIES
THAT HAVE -- THAT ARE CONTINUOUS
VERSUS FENESTRATED VERSUS SIGN
SOY DAL.
SINUSOIDAL.
THIS IS SORT OF, AGAIN, SHOWING
THE CELL POPULATIONS ALONG THE
TOP, AND THEN YOU CAN SEE THESE
CELL TYPE-SPECIFIC FINGERPRINTS
BASICALLY, FOR INSTANCE, FOR THE
LUNG ENDOTHELIAL CELLS, RECEPTOR
EXPRESSION IS HIGH AS ONE
EXAMPLE COMPARED TO ALL THE
OTHER CAPILLARIES.
LYVE1 IS MORE -- THIS IS AN
ILLUSTRATION OF HOW WE CAN PULL
OUT THE DIFFERENT PERSONALITIES
OF THESE TISSUE-SPECIFIC CELL
TYPES.
YOU CAN SAY IT'S ALL VERY WELL
AND GOOD TO UNDERSTAND THE
DIFFERENT SUBSETS IN DIFFERENT
TISSUES AND WHAT ARE SHARED IN
TISSUE-SPECIFIC CHARACTERISTICS
BUT HOW DOES THIS HELP US
UNDERSTAND DISEASE?
ONE WAY OF KIND OF LINKING THIS
HUMAN CELL TYPES WITH HUMAN
DISEASE GENETICS IS BASICALLY
MAPPING ON TO -- MAPPING GWAS
ASSOCIATIONS ON TO THE VESSELS
THAT ARE SPECIFIC FOR THE
DISEASE, SO FOR INSTANCE, FOR
THE AEROCYTES, SO THE LUNG
CAPILLARY ENDOTHELIAL CELLS THAT
ARE ASSOCIATED WITH GAS
EXCHANGE, THE -- ON 1RL1 IS
SPECIFICALLY EXPRESSED IN THAT
ENDOTHELIAL CELL TYPE SO THIS IS
A WAY THAT WE CAN START TO ALSO
UNDERSTAND THE ROLE THAT
VARIATIONS IN GENES MAY PLAY IN
TERMS OF DISEASE ASSOCIATION.
THIS IS SORT OF OBVIOUSLY
SHOWING HOW THAT SUBUNIT OF THE
IL-33 RECEPTOR MAY PLAY A ROLE
IN THE ASSOCIATION OF ASTHMA
THROUGH CHANGES IN ITS AFFINITY
OR SIGNALING WITH THE CYTOKINE.
A NEXT STEP IS ALSO HOW THE
CELLS ARE INTERACTING WITH THE
TISSUE, AND THIS IS COMING BACK
TO INTEGRATING THE TISSUE
ARCHITECTURE FROM SPATIAL
GENOMICS DATA THAT I MENTIONED
AT THE BEGINNING OF THE TALK
WITH ALL OF THIS DATA THAT I'VE
BEEN DESCRIBING SO FAR THAT'S
BASICALLY SUSPENSION SERUM CLEAR
ANALYSIS.
I'M GOING TO JUMP ON TO THE
LYMPHATIC ENDOTHELIAL CELLS THAT
MAY BE OF MOST RELEVANCE FOR
THIS AUDIENCE, AND WHAT WE DID
HERE WAS BASICALLY INTEGRATE OUR
DATA FROM ACROSS THE BODY, AND
THAT INCLUDES INGUINAL LYMPH
NODES, MESENTERIC LYMPH NODES AS
WELL AS LYMPHOID TISSUE FROM
OTHER ORGANS.
THIS ENTIRE LYMPH NODE IS IN
BROWN, INGUINAL LYMPH NODE IS IN
PURPLE AND THEN DETERMINE
DIFFERENT SUBSETS OF THEEL YAL
CELLS IN OUR LARGE INTEGRATED
DATASET.
WHAT WAS VERY HELPFUL WAS THIS
PUBLICATION FROM ABE ET AL.
WHERE THEY STUDIED LYMPHOMA IN
LUNG DISEASE AND LUNG DISEASE
BIOPSIES.
OUR DATA IS A LOT FROM ORGAN
DONOR TISSUES WHERE THERE'S
LARGE CHUNKS OF TISSUE THAT WE
CAN ANALYZE.
WHAT THIS ALLOWS US TO DO IS TO
FIND AT THE MOLECULAR LEVEL THE
DIFFERENT SUBSETS OF LYMPHATIC
ENDOTHELIAL CELLS IN LYMPH
NODES.
YOU CAN SEE SPECIFICALLY HERE IN
DIFFERENT COLORS THE DIFFERENT
ENDOTHELIAL CELLS KIND OF LINING
THE -- 'FESS ELSE, -- VR
MEDULLARY ENDOTHELIAL CELLS
BRIDGE, SINUS ENDOTHELIAL CELLS
AND SO ON.
WHAT WE'RE ABLE TO DO HERE IS
THEN DIG INTO THE MOLECULAR
FINGERPRINT OF THESE DIFFERENT
CELL POPULATIONS AND UNDERSTAND
IN DETAIL SORT OF WHAT
CONSTITUTES THE EXPRESSION
PATTERN OF THESE DIFFERENT
ENDOTHELIAL CELL POPULATIONS.
THIS IS SIMPLY SCRATCHING THE
SURFACE OF THIS DATA, BUT WHAT
WE SEE, FOR INSTANCE, IS THAT
LYVE1 IS EXPRESSED HIGHLY IN THE
MEDULLA, THE LYMPHATIC
ENDOTHELIAL CELLS BUT NOT IN THE
FLOOR, CEILING OR VALVULAR
ENDOTHELIAL CELLS.
THE MEDULLAR IS EXPRESSED IN THE
VALVE AND CORTEX BEING LYMPHATIC
ENDOTHELIAL CELLS, SO THERE'S A
LOT OF BEAUTIFUL MOLECULAR
DETAIL THAT WE CAN STUDY IN MUCH
MORE DETAIL FROM THIS CELL DATA.
SO I'M JUST GOING TO WRAP UP
THERE, AND I HOPE THAT THIS HAS
GIVEN YOU A KIND OF IMPRESSION
OF WHAT WE CAN LEARN FROM BLOOD
AND LYMPHATIC FROM THIS HIGH
RESOLUTION GENOMICS DATA, THAT
WE CAN UNDERSTAND THE ORGAN AND
TISSUE-SPECIFIC FUNCTIONAL
ADAPTATIONS OF THE DIFFERENT
CELL TYPES, AND MAP DISEASE
ASSOCIATIONS AND ALSO DRUG
TARGETS ON TO THESE CELL TYPES
AND START TO UNDERSTAND HOW
DRUGS MAY BE AFFECT BEING THE AE
VASCULATURE.
I MENTIONED BRIEFLY KIND OF
DEFINING VASCULAR CELL TYPES
FROM THERE DATA, END CARD YAL
CELLS, SPLENIC SINUSOIDAL
CAPILLARY ENDOTHELIAL CELLS,
MULL
PULMONARY ARTERY PERICYTES, HOW
THESE BUILDING BLOCKS OF CELLS
INTERACT WITH EACH OTHER TO MAKE
THE VESSELS AND HOW THEY
INTERACT WITH THE OUTSIDE
TISSUE, WHICH YOU CAN OBVIOUSLY
START TO PUT THESE PIECES OF THE
JIGSAW PUZZLE TOGETHER USING THE
SPATIAL GENOMICS DATA AND
INTEGRATING THE SINGLE CELL
GENOMICS.
I WANT TO SAY THANK YOU TO LING
WHO I'VE MENTIONED WHO'S A
TALENTED POSTDOC IN THE GROUP.
SHE'S WORKED WITH ANA-MARIA
CUJBA AND OTHER MEMBERS OF MY
GROUP, MICHAELA NOSEDA.
I WILL FINISH THERE, SAY THANK
YOU AND TAKE ANY QUESTIONS NOW
OR IN THE Q & A SESSION.
THANKS.
>> THANK YOU SO MUCH, SARAH.
THAT WAS ABSOLUTELY EXCELLENT
AND GAVE US A LOT TO THINK
ABOUT.
WE'LL HAVE TO -- THANK YOU
AGAIN.
WE'LL HAVE TO RESERVE THE
QUESTIONS TO THE END OF SESSION
TWO, IF YOU CAN HANG AROUND.
IF NOT, WE'LL DO SOMETHING ELSE,
BUT THANK YOU, SARAH.
I'LL HAND IT OVER TO TIM.
THANK YOU VERY MUCH.
>> GREAT, AND GOOD MORNING,
EVERYONE.
>> I'D BETTER INTRODUCE YOU.
>> OH, SORRY.
SORRY ABOUT THAT.
>> IT'S MY PLEASURE TO INTRODUCE
OUR MODERATOR FOR THIS SESSION,
DR. TIM PADERA, ASSOCIATE
PROFESSOR AT THE MASSACHUSETTS
GENERAL HOSPITAL, WHERE HE
STUDIES LYMPHATIC FUNCTION IN
TUMORS AND OTHER PATHOLOGIC
CONDITIONS.
HE'S DEVELOPED MANY NOVEL TOOLS
AND MADE IMPORTANT PROGRESS IN
UNDERSTANDING TUMOR METASTASIS.
>> THANK YOU FOR INTRODUCING ME
AND THAT KIND INTRODUCTION.
I NOW HAVE THE HONOR OF
INTRODUCING OUR FIRST SPEAKER,
WHO'S ALSO A FRIEND AND
COLLEAGUE HERE IN BOSTON,
DR. DHRUV SINGHAL AT THE BETH
ISRAEL DEACONESS MEDICAL CENTER
OR SCHOOL.
DHRUV, IF YOU'RE ON IF YOU WANT
TO START SHARING YOUR SLIDES AND
WE'RE GOING TO HEAR A JOURNEY
FROM HIM AND HIS TITLE IS
PREVENTING BREAST CANCER-RELATED
LYMPHEDEMA, A SURGEON'S JOURNEY
HIGHLIGHTING THE IMPORTANCE OF
LYMPHATIC ANATOMY.
>> THANKS FOR THAT KIND
INTRODUCTION.
I'D LIKE TO THANK YOU, ZORINA,
SELEN, ANDREA, BABAK, FOR THE
HONOR OF PRESENTING IN THIS
FORUM.
PREVENTING BREAST CANCER-RELATED
LYMPHEDEMA, A SURGEON'S JOURNEY
HIGHLIGHTING THE IMPORTANCE OF
LYMPHATIC ANATOMY, WE'RE GOING
TO BE SHIFTING FROM A MICRO
SCALE TO THE MACRO SCALE, BUT AT
THE VERY END OF THIS TALK, WE'RE
GOING TO GO BACK A LITTLE BIT TO
THE MICRO SCALE.
DISCLOSURE, I DO RUN THE BOSTON
LYMPHATIC SYMPOSIUM, I DO WORK
VERY CLOSELY WITH INDUSTRY IN
THE LYMPHATIC FIELD.
WHILE I DON'T MAKE ANY MONEY
FROM THIS, THEY ARE CRITICAL TO
RUNNING OUR SYMPOSIUM.
THE OUTLINE OF MY TALK, I'M
GOING TO GIVE A LITTLE BIT OF
BACKGROUND ABOUT BREAST
CANCER-RELATED LYMPHEDEMA, AND
THEN I'M GOING TO TALK ABOUT
IMMEDIATE LYMPHATIC
RECONSTRUCTION, WHICH IS A
SURGICAL TECHNIQUE TO TRY TO
PREVENT THE DEVELOPMENT OF
LYMPHEDEMA, AND THEN I'LL TALK
TO YOU ABOUT WHAT KEEPS ME UP AT
NIGHT, WHICH IS LYMPHATIC
ANATOMY AND HOW I BELIEVE
LYMPHATIC ANATOMY PLAYS A
CRITICAL ROLE IN THE PREVENTION
OF THIS DISEASE.
SO FOR BACKGROUND, THERE ARE
ABOUT -- I KNOW THIS IS A MOVING
TARGET, BUT THERE ARE ABOUT
3.8 MILLION BREAST CANCER
SURVIVORS AND 1 IN 5 WILL GO ON
TO DEVELOP LYMPHEDEMA.
WHILE A LYMPHATIC SURGEON AND
COMMUNITY WE REALLY BELIEVE IN
OUR PROCEDURES IN LYMPH NODE
TRANSPLANTATION AND WHILE THERE
ARE GOOD OUTCOMES FROM THIS, I
DON'T THINK THERE'S A SINGLE
LYMPHATIC SURGEON THAT WALKS
AROUND AND CLAIM THAT THEY CAN
RELIABLY AND ACCURATELY
CONSISTENTLY CURE LYMPHEDEMA.
SO GIVEN THE FACT THAT WE KNOW
THAT LYMPHEDEMA IS A PROGRESSIVE
DISEASE, WE WANT TO TRY TO
PREVENT IT, ESPECIALLY IN
DEVELOPED COUNTRIES, WHERE THE
NUMBER ONE CAUSE OF LYMPHEDEMA
OCCURS AT THE TIME OF CANCER
TREATMENT.
SO I WANT TO TALK SPECIFICALLY
ABOUT ILR OR IMMEDIATE LYMPHATIC
RECONSTRUCTION.
WE'LL START WITH A MODERN
HISTORY OF THIS.
SO THIS CONCEPT REALLY BEGAN IN
2007 WHEN A BREAST SURGEON,
DR. KLIMBERG, CAME UP WITH
AXILLARY REVERSE MAPPING WHERE
SHE RECOGNIZED RESECTION IN
BREAST CANCER TREATMENT WAS THE
HIGHEST RISK FACTOR FOR
DEVELOPING LYMPHEDEMA.
SO SHE SAID WHY DON'T WE INJECT
A BLUE DYE INTO THE ARM
LYMPHATICS, LEAVE THE BLUE LYMPH
NODES BEHIND BECAUSE THEY'RE
PRESUMABLY DRAINING THE ARM AND
NOT THE BREAST.
BY DOING SO, THE RATES OF
LYMPHEDEMA DID PRELIMINARILY
PLUMMET DOWN TO THE SINGLE
DIGITS.
THE PROBLEM WAS THOSE BLUE LYMPH
NODES CROSSTALK.
THEY DRAIN NOT ONLY THE ARM BUT
THE BREAST.
AND FOR THAT REASON, THE
ONCOLOGIC SAFETY OF THIS IS
BEING FURTHER TESTED IN A
MULTICENTER TRIAL CURRENTLY
ONGOING.
BUT THE SURGEONS IN ITALY,
DR. BOCCARDO AND CAMPISI IN
2009, SAID LET'S TAKE THIS ONE
STEP FURTHER.
THEY SAID WHY DON'T YOU TAKE OUT
BLUE LYMPH NODES AND AS
LYMPHATIC SURGEONS, WE'LL LET
YOU FIND THE BLUE LYMPHATICS AND
BYPASS IT INTO A VEIN.
AND BY DOING SO, THEY REPORTED
AT FOUR-YEAR FOLLOW-UP WHICH IS
SIGNIFICANT FOLLOW-UP IN THIS
FIELD, AN INCIDENCE OF 4% OF
LYMPHEDEMA IN THE PATIENT
POPULATION.
NOW, THIS IS IN CONTRAST TO
HISTORICAL CONTROL, WHICH REALLY
ARE THE 26 TO 33% RANGE FOR
THEIR PATIENT COHORT, SO THIS IS
QUITE SIGNIFICANT.
I DO WANT TO NOTE THAT THEY TERM
THIS PROCEDURE IN LYMPHA, WE'VE
CHANGED THE NAME OVER TO
IMMEDIATE LYMPHATIC
RECONSTRUCTION.
DR. BOCCARDO IS IN AGREEMENT
WITH THE CHAIK OF THE -- THF
THE NAMING BUT THIS IS THE EXACT
SAME PROCEDURE AS LYMPHA IN THE
LITERATURE.
I WANT TO TALK ABOUT OUR
EXPERIENCE.
TO SHOW OUR EXPERIENCE, I WANT
TO SHOW YOU A VIDEO.
THE ONE IMPORTANT MODIFICATION
WE DID IS WE'VE REALLY
INTRODUCED THESE FLUOROSINE,
THERE ARE A VARIETY OF REASONS
FOR THIS IMPORTANT TO SURGICAL
COMMUNITY AND WE'VE CHANGED OUR
INJECTION SITES.
WE'RE INJECTING IT IN THE ARM
BEFORE WE BEGIN OUR PROCEDURE OF
THE AXILLA -- HERE'S THE ARM
OVER HERE, THE HEAD IS OVER
HERE, AND HERE ARE LEVEL ONE
LYMPH NODES.
USING A SPECIALIZED FILTER ON
OUR MICROSCOPE, WE CAN ACTUALLY
SEE THE FLUROSINE AND HERE THEY
ARE.
WE COME BACK IN AND HERE THEY
ARE.
IF YOU LOOK AT THEM, YOU CAN
ACTUALLY SEE ARM LYMPH IS
SPILLING RIGHT INTO THE DEFECT.
AND WE ISOLATE THESE CHANNELS, E
LITERALLY -- THEM INTO A VEIN.
THIS IS A TEMPORARY STITCH, BUT
IT DOES A JOB IN TERMS OF
POSITIONING THINGS WHERE WE NEED
THEM, AND THEN WE TAKE THE VEIN
AND WE SECURE TO THE
PERILYMPHATIC TISSUE.
WE REMOVE THE INITIAL STITCH, WE
LOOK UNDER THE FILTER, YOU CAN
NOW SEE THE DYE GOING INTO THE
VEIN.
WE REMOVE THE CLAMP, WAIT AN
HOUR DURING A BREAST
RECONSTRUCTION AT THE SAME TIME,
AND WE COME BACK AND WE LOOK,
AND NOW I CAN SEE THAT VEIN IS
FULL OF ARM LYMPH.
SO IN ESSENCE, WE'VE BYPASSED
THE ARM LYMPH INTO A VEIN.
RECENTLY, WE HAD OUR FOUR-YEAR
INSTITUTIONAL EXPERIENCE ON ILR
ACCEPTED IN JOURNAL PRS, AND
JUST TO GET TO THE CRUX OF IT,
WE WERE REPORTING ON 90 PATIENTS
HERE, WE ONLY INCLUDED PATIENTS
WHERE WE HAVE A MINIMUM OF
SIX-MONTH FOLLOW-UP, AND WHERE
WE ACTUALLY SUCCESSFULLY
COMPLETED AN ILR PROCEDURE.
I WOULD LIKE TO NOTE THE
MAJORITY OF THESE PATIENTS GOT
ADJUVANT RADIOTHERAPY, OF WHICH
THE MAJORITY WAS REGIONAL LYMPH
NODE RADIATION, AND AGAIN,
MEDIAN NUMBER OF LYMPH NODES
REMOVED HERE IS AT 14.
SO AGAIN, THE INCIDENCE OF
LYMPHEDEMA USING A SO-CALLED
CONTROL SHOULD BE APPROACHING
ABOUT THE 26% NUMBER.
THIS IS ALL 90 PATIENTS HERE, A
CLEAR CIRCLE REPRESENTS A VISIT
IN OUR CENTER POSTOPERATIVELY, A
CLEAR ONE MEANS THEY DID NOT
MEET THE CRITERIA FOR LYMPHEDEMA
AND DARK CIRCLE MEANS THEY DID.
SO ESSENTIALLY AVERAGE FOLLOW-UP
AT 17 MONTHS, WE HAVE A
FOLLOW-UP RATE AT 9%, AGAIN
AGAINST HISTORICAL CONTROLS,
WHICH SHOULD BE AROUND 26%.
SO THAT'S ILR AND THAT'S OUR
EXPERIENCE, AND NOW I WANT TO
DIVE INTO WHAT KEEPS ME UP AT
NIGHT.
SO WHEN YOU LOOK AT THE
INCIDENCE OF LYMPHEDEMA, WE ALL
KNOW WHAT THE MAIN RISK FACTORS
ARE.
EVEN IF YOU TAKE ALL THREE RISK
FACTORS, ONLY 1 IN 3 ABOUT OR
1 IN 4 WOMEN ARE GOING TO GO ON
TO DEVELOP BREAST CANCER-RELATED
LYMPHEDEMA.
WHY?
THAT'S THE QUESTION THAT KEEPS
ME UP.
WHY ARE 2 OUT OF 3 OR 3 OUT OF ?
THIS IS CRITICAL AND I THINK
THIS WOULD BE A COMPLETE
CLINICAL PARADIGM SHIFT.
THERE'S OFTEN A LOT OF
DISCUSSION, HEALTHY IMPORTANT
DISCUSSION OF SHOULD WELL DO AN
AXILLA RESECTION, SHOULD WE DO
REGIONAL RADIATION.
I THINK IF YOU HAD A LYMPHATIC
EXPERT SITTING IN THE CONFERENCE
ROOM AND YOU WERE ABLE TO SAY,
LOOK, THIS PATIENT'S INDIVIDUAL
RISK AGAIN OF LYMPHEDEMA IS
100%, THAT MY VERY MUCH SHIFT
THE DISCUSSION IN THAT ROOM IN
FAVOR OF THE PATIENT AND
HOPEFULLY PREVENTING THE
DISEASE.
SO WHAT IS THE -- WHY ARE --
WHAT'S THE INDIVIDUAL RISK FOR A
PATIENT GETTING BREAST CANCER
RELATED LYMPHEDEMA?
IF YOU GO INTO THE LITERATURE,
YOU'RE GOING TO FIND TWO BASIC
SCHOOLS.
ONE IS THAT IT'S GENETIC AND
ANOTHER ONE IS THAT THERE'S
ANATOMIC VARIATION.
WHEN I STARTED TALKING ABOUT
THIS, I SAID IT ALL ABOUT
ANATOMY.
I STILL BELIEVE ANATOMY IS
DRIVING THIS BUT I DO THINK
GENETICS PLAY A ROLE AND I'LL
TALK ABOUT WHERE I THINK THAT
MIGHT BE THE CASE.
SO THE KEY THING ABOUT ANATOMY,
IT WAS BROUGHT UP IN INTERDUCK
INTRODUCTORY REMARKS YESTERDAY,
THE LATEST COMPENDIUM -- IF YOU
GO BACK TO THIS ORIGINAL PANEL
FROM SAPPEY IN 1874, YOU CAN SEE
THE MAJORITY OF THE ARM
LYMPHATICS PRETTY EXCELLENT.
BUT HERE WITH THE RED ARROW, YOU
CAN SEE THE PATHWAY COMPLETELY
AVOIDING THE AXILLA.
THIS IS SOMETIMES TERMED THE
LATERAL UPPER ARM PATHWAY,
SAPPEY PATHWAY, IT HAS A LOT OF
NAMES, BUT THIS MIGHT BE
PROTECTED IF SOMEBODY UNDERGOES
AN AXILLA RESECTION AND THIS
PATHWAY IS PRESENT.
SO OUR TEAM GOT INTERESTED IN
THIS AND REALLY STARTED LOOKING
AT THIS A FEW YEARS AGO, AND THE
ANATOMISTS MADE IT CLEAR THAT
THIS PATHWAY IS REALLY RIGHT
ADJACENT TO THE CEPHALIC VEIN SO
USING THE CEPHALIC VEIN AS A
MARKER, USING ULTRASOUND WE
INJECT A DYE INTO THE SKIN SO WE
GET IT INTO THE LYMPHATIC
SYSTEM, AND YOU CAN SEE ON THIS
WITH LYMPHATICS TRULY RIDING
ALMOST RIGHT ALONG THE VEIN.
THERE'S A LOT OF WAYS TO SHOW
THIS.
SUAMI CAME WITH THIS BEAUTIFUL
DISSECTION OF LYMPHATICS, BUT
HERE'S THE BACKUP.
THE M-S PATHWAY.
HERE'S IMAGING IN OUR OWN CLINIC
WE CAN DO PREOPERATIVELY ON A
NEWLY DIAGNOSED BREAST CANCER
PATIENT, WHERE WE CAN DEFINE
THIS, WE CAN DEFINE THEIR M-S
PATHWAY AND ITS PRESENCE OR
ABSENCE.
AND WHAT WE'VE SHOWN IN VIVO IS
WHAT ANATOMISTS HAVE SHOWN IN
CADAVERS YEARS AGO, DECADES AGO,
IN THAT THERE'S VARIATIONS IN
THIS PATHWAY, WHAT WE CALL A
LONG BUNDLE AND A SHORT BUNDLE.
A LONG BUNDLE IS WHERE THIS
PATHWAY EXISTS AND IT TRAVELS
THROUGHOUT THE ARM, WHICH IS
PROBABLY FAVORABLE BECAUSE AT
THIS OTHER MAIN PATHWAY, THE
AXILLA GETS WIPED OUT AFTER AN
AXILLA DISSECTION, THE ENTIRE
ARM CAN PROBABLY USE THIS AS A
BACKUP.
HERE YOU HAVE WHAT WE CALL A
SHORT BUNDLE WHERE YOU INJECT IN
THE HAND FIRST AND ACTUALLY
NOTHING LIGHTS UP OUT HERE WITH
A LATERAL UPPER AND -- YOU HAVE
TO DO AN INJECTION HERE TO SEE
IT.
YOU CAN IMAGINE IN THIS PATIENT
THAT THIS MAIN PATHWAY GETS
WIPED OUT, YOU HAVE THIS
WATERSHED AREA, AND THIS IS
WHERE GENETICS MAY PLAY A ROLE
IN SOME PATIENTS REGENERATING
FASTER THAN OTHERS.
HERE'S A QUICK VIDEO SHOWING
WHAT THIS LOOKS LIKE.
SO THIS IS, AGAIN, WE CAN DO
THIS IN OUR CLINIC, WE INJECT
THE HAND FIRST AND RIGHT AWAY,
YOU CAN SEE BOTH PATHWAYS ARE
SHOWING UP.
WE HAVE OUR MAIN PATHWAY HERE
GOING TO THE AXILLA, AND THERE'S
A BACKUP PATHWAY, HERE IT IS,
IT'S CONNECTED TO THE FOREARM.
THIS IS FAVORABLE.
NOW I'LL SHOW YOU WHAT IT LOOKS
LIKE IN A SHORT BUNDLE BETTER.
SO WE INJECT THE HAND AND
ACTUALLY NOTHING LIGHTS UP HERE.
WE HAVE TO DO A SECOND INJECTION
UP HERE TO MAKE THESE OTHER
PATHWAYS LIGHT UP.
AND HERE'S YOUR WATERSHED AREA,
ASSUMING THESE PATHWAYS GO AWAY
AFTER AN AXILLARY DISSECTION.
SO WE LOOKED AT PATIENTS AND
ESSENTIALLY TWO THIRDS HAVE A
LONG BUNDLE, WHICH WE BELIEVE IS
GOOD, A THIRD HAS A SHORT BUNDLE
AND STARTING TO NOTICE THE
PRESENCE OF LYMPHEDEMA AND VERY
FEW ACTUALLY HAVE NO BUNDLE AT
ALL.
WHAT WE NOTICED IS EVEN THOUGH
THE SHORT BUNDLE, WHICH IS
UNFAVORABLE, ONLY MADE UP
ONE-THIRD OF OUR COHORT, IT MADE
UP TWO THIRDS OF THOSE PATIENTS
WHO POST OP DEVELOPED ANYTHING
CONSISTENT WITH LYMPHEDEMA.
I WON'T SAY THEY HAD A DIAGNOSIS
OF LYMPHEDEMA BECAUSE WE HAD
PRETTY STRICT CRITERIA AND THEY
MIGHT NOT HAVE FIT ALL THE
CRITERIA, BUT THEY HAD ENOUGH
THAT WE WERE CONCERNED AND WE
MIGHT HAVE EVEN INTERVENED.
SO FORTUNATELY WITH THIS DATA
AND THIS EXPERIENCE, WE WERE
FORTUNATE TO GET FUNDING FROM
THE NIH/NHLBI TO DO FURTHER
STUDY ON THIS PATHWAY, WHERE
WE'RE DEFINING ITS INCIDENCE IN
A HEALTHY FEMALE POPULATION, AS
WELL AS BREAST CANCER SURVIVORS
WHO DID NOT GET LYMPHEDEMA AND
WE ALSO HAVE AN ANIMAL MODEL
WHERE WE WERE LOOKING AT
LYMPHATIC FUNCTION AND MAPPING.
I JUST WANTED TO SHOW SOME
IMAGES FROM PATIENTS THAT ARE
GOING THROUGH RIGHT NOW, THROUGH
OUR R01 MECHANISM, AND WHAT WE
ARE DOING, WHAT YOU ARE NOT
SEEING HERE, WE'RE TAKING OUR
IMAGING AND BASED ON THE ZONE
WHERE WE INITIALLY INJECTED, WE
IS A LYMPHOZONE CONCEPT
INTRODUCED BY SUAMI, YOU SEE
DIFFERENT COLORS.
DIFFERENT COLORS REPRESENT
DIFFERENT ZONES.
I WANT TO POINT OUT THIS LATERAL
UPPER ARM PATHWAY AND I WANT YOU
TO SEE THAT IN DIFFERENT
PATIENTS, WE ARE FINDING THAT
THEY HAVE DIFFERENT
CONTRIBUTIONS IN DIFFERENT
ZONES, AND ULTIMATELY, WE
BELIEVE THIS IS GOING TO PLAY AN
IMPORTANT -- IT'S GOING TO HELP
FILL IN THE GAP OF WHY CERTAIN
WOMEN ARE GETTING LYMPHEDEMA AND
OTHERS ARE NOT AFTER AN AXILLARY
NODE DISSECTION.
WE'RE BACKING THIS UP WITH
NUCLEAR INJECTIONS IN THESE
DIFFERENT ZONES, AND HERE WE
HAVE ISOLATED INJECTIONS IN THIS
ONE VOLUNTEER RIGHT OVER THE M-S
PATHWAY, WHERE YOU CAN SEE EVEN
BETWEEN LEFT AND RIGHT, THERE'S
VARIABILITY ON WHICH NODE LIGHT
UP, VERSUS IN THIS IMAGE, THEY
COME BACK A FEW DAYS LATER,
AFTER THE TECHNICIANS -- WE DO
SEPARATE INJECTIONS, HERE WE DO
IT IN THE HAND AND YOU CAN SEE
DIFFERENT LYMPH NODES ARE
LIGHTING UP.
SO THIS IS REALLY IMPORTANT AS
WE'RE TRYING TO TEASE OUT TRULY
THE ENTIRE PATH, NOT ONLY IN THE
ARM, BUT WHERE DOES THIS GO INTO
THE TORSO?
WE'VE BEEN REALLY FORTUNATE THIS
SUMMER TO RECEIVE FURTHER
FUNDING AS PART OF THE
INCREDIBLE HUBMAP PROGRAM AT THE
NIH, AND WE'VE PUT TOGETHER A
TEAM REALLY LED BY MYSELF,
GIANNIS, SPATIAL TECHNOLOGY UNIT
WHERE WE'RE GOING TO DO MAPPING
OF THE HUMAN LYMPHATIC VESSELS
AND THE GOAL IS TO DO IT
ULTIMATELY THROUGHOUT THE HUMAN
BODY AND HOPEFULLY THROUGHOUT
ALL ORGANS.
WE'RE GOING TO BE OBTAINING 3D
MRLs, ULTIMATELY TAKING THESE
VOLUNTEERS TO THE O.R., TAKING
OUT A SEGMENT THAT'S PREDEFINED
IN THE MRL, AND THEN DOING
SPATIAL ANALYSIS ON IT,
REGISTERING BIOMOLECULAR ASSAYS
BACK TO OUR 3D MRI.
SO WITH THAT, IN CONCLUSION, YOU
KNOW, I BELIEVE ILR REDUCES
LYMPHEDEMA INCIDENCE, AND I
THINK LYMPHATIC ANATOMY STUDY IS
GOING TO BE CRITICAL FOR THE
FUTURE OF THIS FIELD, NOT ONLY
FOR PREVENTION BUT I BELIEVE
WE'LL BE ABLE TO REVERSE
ENGINEER SOLUTIONS ONCE WE
UNDERSTAND WHERE THE ANATOMIC
GAPS ARE, WE'LL BE ABLE TO
BETTER DECIDE ON HOW WE SHOULD
APPROACH PATIENTS THAT ALREADY
HAVE THE DISEASE SURGICALLY, IN
OTHER WORDS.
GAPS, NEED AND OPPORTUNITIES,
HOW CAN WE STRATEGIZE FURTHER TO
IMPROVE THE SURGICAL TECHNIQUE
AND SURGICAL PREVENTION OF
LYMPHEDEMA?
NUMBER TWO, AND THIS IS THE ONE
THAT I REALLY THINK ABOUT ALL
THE TIME, WHAT ARE THE MAIN
LYMPHATIC ANATOMY VARIANTS OF
THE UPPER EXTREMITY, AND THEN
THE COROLLARY IS, HOW DO THE
PRESENCE OR ABSENCE OF EACH
VARIANT CONTRIBUTE TO THE
INCIDENCE OF LYMPHEDEMA?
I WANT TO THANK THE CLINICAL
TEAM HERE, AT THE BOSTON
LYMPHATIC 16 TE THE RESEARCH CEH
TEAM.
WE HAVE INCREDIBLE SUPPORT FROM
THE NIH, THE JOBST LYMPHATIC
RESEARCH GRANT HAS A
SCHOLARSHIP, I WANT TO THANK OUR
COLLABORATORS, ESPECIALLY TIM,
FOR THOSE WHO ARE INTERESTED, WE
RUN OUR OWN SYMPOSIUM, AND OUR
NEXT CLINICAL AND RESEARCH
PROGRAM WILL BE IN 2023.
THANK YOU AGAIN.
>> AWESOME.
THANK YOU SO MUCH, DREW, FOR
THAT WONDERFUL PRESENTATION.
WE WILL HAVE YOUR QUESTIONS AT
THE END OF THE WHOLE SESSION AND
I'VE ALREADY SEEN SOP STARTING G
TO COME IN, SO HE WITH LOOK
FORWARD TO BE ABLE TO HAVE THAT
DISCUSSION WITH YOU THEN.
SO NEXT I AM HONORED TO
INTRODUCE OUR NEXT SPEAKER, WHO
IS MARC SCHAVERIEN.
MARC, IF YOU WANT TO PULL UP
YOUR SLIDES.
MARC IS FROM THE MD ANDERSON
CANCER CENTER, TELLING US ABOUT
OUTCOMES OF VASCULARIZED LYMPH
NODE TRANSPLANT FOR LYMPHEDEMA
TREATMENT.
MARC, THE FLOOR IS YOURS.
>> THANK YOU VERY MUCH INDEED,
TIM.
CAN I JUST CHECK, YOU CAN HEAR
ME AND SEE MY SLIDES?
>> WE SEE YOUR SLIDES AND HEAR
YOU WELL.
THANK YOU.
>> PERFECT.
THANK YOU.
WELL, IT'S A REAL HONOR TO BE
PART OF THIS MEETING.
IT'S BEEN A REALLY FASCINATING
TWO DAYS.
I'M LEARNING A LOT.
I HAVE A BOOK BUT I DON'T ACCEPT
FEES OR ROYALTIES.
AND TODAY I'M GOING TO TALK TO
YOU ABOUT VASCULARIZED LYMPH
NODE TRANSPLANTATION WHICH IS
REALLY THE PREDOMINANT VIABLE
TREATMENT WE HAVE FOR
ESTABLISHED LYMPHEDEMA.
I ALSO WANT TO TALK ABOUT AN
APPROACH THAT WE HAVE FOR
PREOPERATIVE OPTIMIZATION WHICH
SEEMS TO REALLY IMPROVE OUTCOMES
FROM THIS.
SO AS WE ALL KNOW AND THIS IS
WHY WE'RE HERE AT THIS MEETING,
LYMPHEDEMA IS A SEVERE CHRONIC
PROGRESSIVE DEBILITATING DISEASE
FOR PATIENTS CHARACTERIZED IN
ITS ADVANCED FORMS BY THIS
CHRONIC PHENOTYPE OF
PREDOMINANTLY FIBER ADIPOSE
EXCESS CHARACTERIZED BY CHRONIC
INFECTIONS.
AND VASCULARIZED LYMPH NODE
TRANSPLANTATION, ALTHOUGH IT'S
BEEN AROUND FOR QUITE SOME TIME,
IT'S ONLY RECENTLY THAT WE'VE
ESTABLISHED QUITE A BODY OF
EVIDENCE SUPPORTING ITS
EFFECTIVENESS.
BUT WHEN WE LOOK AT THE DATA
THAT'S AVAILABLE, THERE ARE
THREE SYSTEMATIC REVIEWS THAT
DEMONSTRATE IMPROVEMENT IN
VOLUME REDUCTION, PATIENT
SYMPTOMS, QUALITY OF LIFE
REDUCTION OF IB FECTED INF.
WHEN WE COMPARE THE RESULTS OF
SURGERY WITH THOSE OF
CONSERVATIVE THERAPY ONLY,
INCLUDING IN A RANDOMIZED
CONTROL TRIAL, THERE ARE
IMPROVEMENTS, SIGNIFICANT
IMPROVEMENTS FROM SURGERY WHEN
COMPARED WITH CONSERVATIVE
THERAPY ALONE.
SO THE APPROACH I'M GOING TO
DISCUSS WITH YOU TODAY IS FROM
MD ANDERSON.
IT'S REALLY IMPORTANT TO HAVE A
MULTIMODAL METHOD FOR PATIENT
EVALUATION, AS NOT ONE MODE IS
OPTIMAL OR RELIABLE FOR
DIAGNOSIS, FOE KUTIONING Y
AND CLINICAL EXADGES TO
DETERMINE THE PATIENT REALLY HAS
LYMPHEDEMA AS COMMONLY SWELLING
IS ATTRIBUTED TO OTHER
CONDITIONS.
A REALLY IMPORTANT PART OF THIS
AS DHRUV WAS JUST DISCUSSING IS
IMAGING, ICG IN PARTICULAR BUT
ALSO MAGNETIC RESONANCE
LYMPHOGRAPHY, IT'S IMPORTANT TO
STANDIZE MEASUREMENTS, WE USE A
PEROMETER, YOU CAN ALSO USE A
TAPE MEASURE, BIOIMPEDANCE
SPECTROSCOPY IS REALLY BECOME BG
A TOOL IN MEASURING THE FLUID
CHANGES IN THESE PATIENTS, AND
ALSO PATIENT-REPORTED OUTCOMES.
THERE ARE MANY DIFFERENT TOOLS.
WE USE THE NLIS.
THERE IS OFTEN A CO-MORBID
ELEMENT, MAY BE TREATED PRE-OP
PHILADELPHIA TO OPTIMIZE
OUTCOMES IN SURGERY, AND THAT
CAN BE -- BUT SIMPLY REQUIRES
VENOGRAPHY.
WE'RE EVALUATING THE THE DERML
BACKFLOW.
THIS IS THE MD ANDERSON SCALE,
RELIABLY -- IT'S IMPORTANT TO
CONFIRM THAT PATIENTS HAVE
LYMPHEDEMA THROUGH DIAGNOSTIC
LYMPHATIC IMAGING TO EXCLUDE
OTHER CAUSES OF LIMB SWELLING.
THOSE PATIENTS ARE POTENTIALLY
CANDIDATE FOR VASCULARIZED FLOW
TRANSPLANT.
PATIENTS WITH CANCER AREN'T
TYPICALLY CANDIDATES FOR THESE
THERAPIES, NOR THAT'S WITH
SEVERE UNTREATABLE VENOUS INFUF
SEE.
INSUFFICIENCY.
THESE SURGERIES ARE POTENTIALLY
LONG, AND PATIENTS MAY REQUIRE
RETURN TO THE O.R., SO IT'S
IMPORTANT TO OPTIMIZE CARDIOPULL
CARDIOPULMONARY ECOMORBIDDITIES.
PATIENT WITH HIGH OBESITYTIOUS
BE ON A WEIGHT-LOSS PROGRAM TO
LESSEN RISKS FROM SURGERY.
THIS IS HIS APPROACH TO SUCK
SHN-ASSISTED LIE
SUCTION-ASSISTED LIPECTOMY.
FROM THAT TRANSLATED THAT INTO
VASCULARIZED LYMPH NODE
TRANSPLANTATION, EVERY PATIENT
REQUIRES A SLIGHTLY DIFFERENT
APPROACH.
REALLY CENTRALLY, COMPLIANCE
WITH OPTIMIZED CUSTOM
CONSERVATIVE THERAPY, AIDS
PATIENT SELECTION, ALSO IT
IMPROVES THE CONDITIONS FOR
SURGERY BY TRANSITION TOWARDS
THE MAINTENANCE PHASE.
AND ALSO IT ALLOWS US TO
INDEPENDENTLY EVALUATE THE
OUTCOMES FROM SURGERY AS OPPOSED
FROM CONSERVATIVE THERAPY.
WEIGHT MANAGEMENT MAY REQUIRE
REFERRAL TO A NUTRITIONIST OR
DIETITIAN, SOMETIMES TO
BARIATRIC SURGEON.
WITH PATIENTS WITH FREQUENT
EPISODES OF CELLULITIS, IT MAY
BE NECESSARY TO GIVE
PERIOPERATIVE ANTIBIOTICS.
THIS IS TYPICALLY WHAT A PATIENT
WILL EMBARK ON.
WHEN THEY PRESENT, WE WILL
REDUCE THEM USING EITHER
BANDAGING OR SPECIALIZED
COMPRESSION GARMENTS UNTIL
THERE'S MINIMAL OR NO PITTING
EDEMA.
THEY ARE MAINTAINED TIM
TIPICALLY IN CUSTOM COMPRESSION
GARMENTS.
OCCASIONALLY PATIENTS CAN BE
MANAGED IN NON-CUSTOM GARMENTS.
SOMETIMES PATIENTS WILL ALSO GET
A PUMP.
IT IMPORTANT TO UNDERSTAND THESE
PATIENTS ARE VERY COMPLEX AND
THEY MUST BE MANAGED IN
MULTIDISCIPLINARY
PATIENT-CENTERED APPROACH.
REALLY OPTIMIZING THEM IN
CONCERT WITH ONCOLOGY, MEDICINE,
OBVIOUSLY PT AND OT.
AND IT'S IMPORTANT TO ENROLL
THESE PATIENTS IN POSSIBLE
RESEARCH STUDY, WE HAVE MANY
MORE QUESTIONS THAN WE HAVE
ANSWERS, AND REALLY THIS IS THE
MODEL OF THE LE&RN CENTER OF
EXCELLENCE OF WHICH WE'RE A
PART.
SO IN TERMS OF SURGICAL
TREATMENTS, IT'S IMPORTANT TO
UNDERSTAND THE PROCESS OF
LYMPHEDEMA, STARTING AS A
CONDITION OF LYMPHATIC FLUID
STASIS, THEN PHASE IN
INFLAMMATION, MY BRO CYST AND
FINALLY ADD ADIPOSE TISSUE
DIFFERENTIATION.
SO THEN WE CAN CONSTRUCT AN
EVIDENCE-BASED TREATMENT
ALGORITHM BASED OFF PUBLISHED
STUDIES, WHEREBY EARLY STAGE
LYMPHEDEMA, ARE THESE PATIENTS
CANDIDATES FOR BYPASS FROM AREAS
WHERE THE FLUID IS DEPOSITING
INTO ADJACENT VENULES.
THIS IS A MICRO SURGICAL
PROCEDURE INTRODUCING NEW
LYMPHATIC FUNCTION IN THE
AFFECTED EXTREMITY FROM LYMPH
NODES WHERE THEY CAN BE SPARED
AND ADVANCED STAGE PATIENTS WILL
REQUIRE DEBULK WILLING
PROCEDURES, AND THEN LATE STAGE,
THEY MAY BE CANDIDATES FOR
TRANSPLANT PROCEDURE.
SO WE NOW HAVE MANY VASCULARIZED
LYMPH NODE TRANSPLANT OPTIONS
AVAILABLE.
AND UNFORTUNATELY THERE'S NO
OPTIONAL TRANSPLANT SO IT ALWAYS
CAREFUL CONSIDERATION OF THE
ADVANTAGES AND DISADVANTAGES AND
ALSO CONSIDERING THE RELATIVE
REQUIREMENTS OF THE RECIPIENT
AND THE PATIENT BODY HABITUS AND
WHAT THEY HAVE AVAILABLE BASED
ON PREVIOUS SURGERIES.
JUST AS IN PREHABL TAITION, IT
IS EQUALLY IMPORTANT PATIENTS --
FOR PROXIMAL TRANSPLANTATION
INTO THE GROIN OR THE AXILLA,
THAT WILL BE TWO WEEKS
FOLLOWING -- FOREARM, THEY
REQUIRE FOUR WEEKS, AND THEN
THEY GET BACK INTO THEIR -- WE
TAKE PATIENTS OUT OF THEIR
GARMENTS AND MEASURE THEM.
IT'S IMPORTANT AGAIN THAT
PATIENTS MAINTAIN STABLE WEIGHT.
THIS CAN BE A COMMON CAUSE OF
REBOUND.
AND SO WE LOOKED AT A
PROSPECTIVE SINGLE SURGEON
SERIES THAT WAS INDEPENDENTLY
ANALYZED OF PRIMARY AND
SECONDARY LYMPHEDEMA PATIENTS,
THEY UNDERWENT -- PATIENTS THAT
UNDERWENT LIPECTOMY WERE
EXCLUDED.
THE VOLUME OF THE EXTREMITY.
WE MEASURED THEM AT STANDARDIZED
PERIOD POSTOPERATIVELY, LOOKING
AT LYMPH VOLUME CHANGE USING
PROMETER.
FOR MAJORITY OF THE PATIENTS THE
SOZO AND WE ALSO MEASURED
PATIENT-REPORTED OUTCOME
MEASURES USING THE LLIS AND ALSO
MEASURES OF PATIENT-REPORTED
FUNCTIONAL OUTCOMES, USING THE
QUICK DASH AND THE LEFS AS
APPROPRIATE.
THERE WERE 134 PATIENTS.
OF NOTE, ALMOST HALF OF THEM HAD
A BMI OF OVER 30 BUT THAT IS
TYPICALLY OUR PATIENT POPULATION
IN TEXAS.
THE MAJORITY HAD SECONDARY
LYMPHEDEMA.
AND 35% HAD A HISTORY OF EPISODE
OF CELLULITIS.
THE PREDOMINANTLY PATIENTS WHO
ARE GETTING GROIN LYMPH NODE
TRANSPLANTATION, TYPICALLY THIS
WAS PART OF ABDOMINAL FLAP
RECONSTRUCTION ALTHOUGH AS YOU
CAN SEE THE NUMBERS WERE FAIRLY
OTHERWISE SIMILAR.
BUT NOTE THAT OVER HALF OF THE
PATIENTS ALSO GOT SYNCHRONOUS
LYMPHOVENOUS BYPASS WHICH IS
TYPICAL IN OUR PATIENT
POPULATION AND I'M HAPPY TO TALK
ABOUT LATER ON.
AND THE OUTCOMES WE SAW VARIOUS
REDUCTIONS IN -- THROUGH 24
MONTHS.
AND THE DATA OVERALL
DEMONSTRATES THAT THE OUTCOMES
FROM THE VASCULARIZED LYMPH NODE
TRANSPLANTS WERE SIMILAR.
I THINK THAT AS WE COLLECT MORE
LONG TERM DATA, WE WILL START TO
NOTICE A BIT MORE OF A
DIFFERENCE BETWEEN THESE
DIFFERENT TRANSPLANTATION
OPTIONS.
AND WE NOTED THAT OUTCOMES WERE
BETTER FOR THE OPPORTUNITY IN
THE LOWER EXTREMITY AND THIS IS
TYPICALLY BECAUSE THE LOWER
EXTREMITY IS A SIGNIFICANT
COMPONENT OF VENOUS
INSUFFICIENCY -- WHEN WE LOOKED
AT COMPLICATIONS, THE
COMPLICATION RATE WAS LOW, THERE
WERE NO FLAP LOSSES AND -- OF
THE DONOR EXTREMITY WHERE THE
LYMPH NODES -- BASIN.
AND SO 24 MONTHS POSTOPERATIVELY
WE FOUND MINIMAL CLINICALLY
IMPORTANT DIFFERENCES FOR LIMB
VOLUME CHANGE, AN LDEX SCORE IN
91% OF PATIENTS, PERHAPS MOST
SIGNIFICANTLY REDUCTION OF
CELLULITIS BY 98%, PERHAPS THE
MOST EXCITING PARTS OF THIS
STUDY, AND THIS HAS BEEN FOUND
BY OTHER GROUPS AS WELL.
THE OUTCOMES I MENTIONED WERE
SIMILAR BETWEEN THE DIFFERENT
LYMPH NODE FLAPS.
AND WHEN WE LOOKED AT
COMPRESSION THERAPY, WE HAVE
EXTREMELY STRICT CRITERIA FOR
REMOVING PATIENTS FROM
COMPRESSION, SO OUR NUMBERS MAY
BE SLIGHTLY LOWER THAN OTHER
GROUPS BUT WE FOUND THAT 63% HAD
EITHER DISCONTINUED OR
SIGNIFICANTLY REDUCED THEIR USE
OF COMPRESSION GARMENTS AT A
MEAN OF A YEAR POSTOPERATIVELY.
WE HAVE SIGNIFICANT KNOWLEDGE
GAPS, WHICH WE ARE AIMING TO
ANSWER.
WE NEED LONGER TERM OUTCOMES.
MY EXPERIENCE SINCE DOING THIS
STUDY AND FROM OTHER DATA THAT'S
COMING OUT FROM OTHER
INSTITUTIONS SEEMS TO SHOW THERE
IS A LONG-TERM STABILITY TO THE
OUTCOME, AND CERTAINLY WE SEE A
PROGRESSIVE IMPROVEMENT
THROUGHOUT -- CAN BE OFTEN
SEVERAL YEARS SINCE THE SURGERY,
AND BUT WE NEED TO PROPERLY
EVALUATE THAT.
WE ALSO NEED TO DETERMINE WHICH
PATIENTS BENEFIT FROM
VASCULARIZED TRANSPLANTATION
BECAUSE CLEARLY SOME DON'T.
THERE ARE SOME THAT SEEM TO BE
HIGHLY SIGNIFICANT INFLAMMATORY
COMPONENTS TO THEIR LYMPHEDEMA
AND THEY APPEAR TO BE DIFFICULT
TO TREAT WITH TRANSPLANTATION.
WE ALSO NEED LARGE SCALE
PROSPECTIVE TRIALS TO DETERMINE
THE OPTIMAL TREATMENT
ALGORITHMS, WHETHER WE SHOULD BE
DEBULK WILLING PATIENTS
DEBULKING OR PERFORMING SURGERY
FIRST AND DEBULK WILLING THEMBU.
ALSO AS WE ARE STUDYING THROUGH
A FUNDED GRANT CURRENTLY, I KNOW
OTHERS ARE LOOKING AT THIS AS
WELL, WE NEED TO STATE THE
MECHANISMS OF OF IMMUNOMODULAN
FOLLOWING THESE SURGERIES
BECAUSE THERE'S A REALLY
FASCINATING IMMUNOMODULATION
COMPONENT TO THESE SURGERIES AND
THROUGH THIS WILL AID IN OUR
DEVELOPMENT TO --
PHARMACOTHERAPIES.
WITH THAT, THANK YOU AND I LOOK
FORWARD TO ANY QUESTIONS.
>> THANK YOU, MARC, FOR YOUR
BEAUTIFUL PRESENTATION.
WE'LL TAKE QUESTIONS FOR YOU
ALSO AT THE END OF THE ENTIRE
SESSION.
SO IT NOW MY PLEASURE TO
INTRODUCE RACHELLE CRESCENZI.
RACHELLE, IF YOU CAN START
PULLING UP YOUR SLIDES.
RACHELLE HAS A LITTLE BIT OF
CHANGE OF TOPIC BECAUSE WE'VE
BEEN TALKING ABOUT TREATMENT OF
LYMPHEDEMA, NOW ONE OF THE MAIN
COMPLAINTS FOR PATIENTS WITH
LYMPHEDEMA HAS ALSO BEEN AND
LIPEDEMA -- WE LOOK FORWARD TO
HER TALK.
RACHELLE IS AT VANDERBILT
UNIVERSITY AND HER TITLE IS
TRANSLATIONAL IMAGING OF SODIUM
AND ADIPOSE TISSUE IN LYMPHEDEMA
AND LIPEDEMA.
SO THE FLOOR IS YOURS.
>> THANK YOU SO MUCH FOR THE
OPPORTUNITY TO SPEAK TODAY.
I WILL BE TALKING ABOUT
TRANSLATIONAL IMAGING IN
LYMPHEDEMA AND LIPEDEMA.
IN THE FIRST PART OF MY TALK
I'LL SHARE ABOUT SOME
DEVELOPMENTS IN NONINVASIVE
IMPANELING OF LYMPHATIC
PHYSIOLOGY AND WHAT THES CAN
TELL US ABOUT LYMPHEDEMA AND
LIPEDEMA AND I'LL FINISH UP WITH
SOME GAPS AND OPPORTUNITIES IN
THIS SPACE.
I HAVE NOTHING TO DISCLOSE OTHER
THAN THE FACT THAT I'M NOT A
CLINICIAN SO THE RESEARCH DATA
PRESENTED IS NOT INTENDED TO
INFORM AN INDIVIDUAL'S MEDICAL
CARE.
SO TODAY WE'LL BE TALKING ABOUT
SODIUM IN THE BODY.
WHILE WE THINK ABOUT SODIUM, WE
TEND TO THINK ABOUT OUR DIETARY
SODIUM INTAKE AND OUR URINE
EXCRETION OF SODIUM, BUT IT'S IN
BETWEEN THAT THERE ARE ME CAN
MECHANISMS IN THE CIRCULATION
AND RENAL FILTRATION THAT CAN
IMPACT SODIUM HANDLING IN THE
BODY AND TODAY WE'RE GOING TO
FOCUS ON LYMPHATIC CIRCULATORY
SYSTEMS THAT CAN MANIFEST IN
SODIUM TISSUE STORAGE.
SO SPECIFICALLY IN THE SKIP,
THESE ARE JUST SOME OF THE
MARKERS THAT PARTICIPATE IN
SODIUM HANDLING.
FOR INSTANCE, SODIUM CAN BIND TO
NEGATIVELY CHARGED SPECIES LIKE
GA AGs AND IS ALSO PARTLY
CLEARED THROUGH THE LYMPHATICS.
WHAT WE KNOW ABOUT LYMPHATIC
CLEARANCE OF SODIUM AND OTHER
MACRO MOLECULES PRIMARILY COMES
FROM PRE-CLINICAL STUDIES AND
ANIMAL MODEL SYSTEMS.
I'M SHOWING AN EXAMPLE HERE OF A
3D RENDERING OF LYMPHATIC
VESSELS IN THE MOUSE SKIN AND
THIS IS COMPARED TO LYMPHATIC
VESSELS VIEWED IN SKIN WITH HIGH
SODIUM.
YOU CAN SEE IN THIS CASE THE
VESSELS ARE DILATED, THERE'S
MORE OF THEM, THERE'S MORE
BRANCHING, AND SO THIS STUDY
REALLY SHOWED LYMPHATIC VESSELS
GROW IN RESPONSE TO A HIGH
SODIUM DIET.
THIS GROUP ALSO WENT ON TO SHOW
LYMPHATIC FUNCTION IS ESSENTIAL
TO CLEAR SODIUM FROM TISSUE AND
WE ALSO KNOW LYMPHATICS
TRANSPORT AND METABOLIZE
LIPOPROTEINS AND FATTY ACIDS IN
LARGE MACRO MOLECULES.
THERE'S STILL A QUESTION WHETHER
THIS PHYSIOLOGY HAS RELEVANCE TO
THE HUMAN CONDITION AND HOW IT
CAN IMPACT PATIENTS WITH
LYMPHATIC DISEASES.
SO FOR THAT, WE REALLY NEED SOME
TRANSLATABLE TECHNOLOGIES THAT
CAN BE APPLIED IN PATIENTS, SO
OVER THE PAST FEW YEARS, I'VE
HAD THE PRIVILEGE OF WORKING
WITH AN AN AMAZING GROUP OF
SCIENTISTS AND PHYSICIANS AT
VANDERBILT WHO CARE FOR PATIENTS
WITH LYMPHATIC DISEASES AND WANT
TO SEES THESE TECHNOLOGIES IN
THE CLIN.
CLINIC.
IN THE FIRST PART EVER MY TALK
I'LL GO THROUGH SOME OF THE
NONINVASIVE METHODS WE'VE BEEN
WORKING TO DEVELOP IN A WHOLE
BODY MANNER FOR LYMPHATICS.
WE FIRST STARTED OUT BY
MEASURING THE FUNDAMENTAL
PARAMETERS FOR SETTING IMAGE
CONTRAST BY MRI IN LYMPH NODES
THEMSELVES AND VISUALIZING THESE
STRUCTURES, THEN WE USED THESE
PARAMETERS TO MOTIVATE AND
DEVELOP CONTRAST FOR
NON-TRASER-BASED MR LYMPH
ANGIOGRAPHY.
THIS IS SHOWN IN THE UPPER TORSO
IN AN EXAMPLE OF A PATIENT WITH
BREAST CANCER LYMPHEDEMA, THEY
HAD UNILATERAL LYMPHEDEMA.
YOU CAN SEE THE IMAGE CONTRAST
HAS HYPERINTENSITIES WHERE
THERE'S TISSUE EDEMA IN THE
LATERAL SENSE.
WE CAN VISUALIZE THE LARGEST
LYMPHATIC DUCT IN THE BODY HERE
SHOWING THE THORACIC DUCT.
THIS METHOD CAN ALSO BE
TRANSLATED TO THE LOWER
EXTREMITIES WHERE WE HAVE
ABILITIES TO MEASURE TISSUE
COMPOSITION, SO FAT WEIGHTED
IMAGING AND SODIUM MRI.
THAT'S WHAT I'LL DESCRIBE NEXT
IN DETAIL IS SOME OF THESE
METHODS IN THE LOWER
EXTREMITIES.
SO WHEN I -- I WILL PRESENT
TODAY SEVERAL DATASETS USING
STANDARDIZED SODIUM MRI AND WHEN
I SAY STANDARDIZED, I WANT TO BE
CLEAR WHAT THAT MEANS.
ALL OF THE SODIUM THAT WE VIZ
LIESH ON MRI IS NATURALLY
OCCURRING SODIUM, 20NA.
WE STANDARDIZED WHERE BELOW THE
CALF ARE PLACED FOUR SOLUTIONS
OF STANDARD SALINE WITH KNOWN
CONCENTRATIONS IN THE
PHYSIOLOGICAL RANGE, SO FROM 10
TO 40 MILL EE 40 MILLIMOL.
SIMILAR CONTRAST ON A WATER
WEIGHTED CONVENTIONAL MRI.
WE CALIBRATE EVERY INDIVIDUAL'S
SKIN AND EACH PIXEL AGAINST
KNOWN STANDARD SALINE IN ORDER
TO PRODUCE A QUANTITATIVE AND
STANDARDIZED TISSUE SODIUM
CONTENT MAP.
WE CAN ALSO MEASURE THINGS BY
IMAGING LIKE ADIPOSE TISSUE
VOLUME QUANTIFICATION PRETTY
EASILY.
YOU CAN IDENTIFY MANUALLY
REGIONS OF INTEREST ON THESE
IMAGES, IN OUR CASE WE'RE
INTERESTED IN THE SKIN, IN THE
MUSCLE AND THE SUBCUTANEOUS ADD
TOES TISSUE OR SAT.
YOU CAN ALSO MEASURE THE VOLUME
AND TISSUE SODIUM CON AT THE
PRESENT TIME AND YOU CAN COMBINE
DIFFERENT VOLUMES TO CREATE A
METRIC -- ONE OF MY -- THE
METRICS THAT I USE AND TALK
ABOUT IS FAT TO WATER VOLUME
RATIO.
SO WHAT CAN BECOME INTERESTING
IS TO PAIR THEM WITH VASCULAR
IMAGING WITH NONINVASIVE MR
LYMPHANGIOGRAPHY.
THIS PATIENT HAS BILATERAL
LIPEDEMA AND YOU CAN SEE ON THIS
CONTRAST, WE CAN VISUALIZE LYMPH
NODE CLUSTERS AND VESSELS GOING
INTO THE INGUINAL SECTION SHOWN
IN THE OVAL.
WE CAN ALSO VISUALIZE
SUBCUTANEOUS TISSUE LYMPHEDEMA.
TISSUE EDEMA.
MOST OCCURS AT THE DISTAL
EXTREMITIES AT THE LEVEL OF THE
CALF WHERE SODIUM QUANTIFICATION
ARE PERFORMED.
FOR THE NEXT PART OF MY TALK,
I'LL DESCRIBE HOW THESE IMAGING
METHODS ARE BEING IMPLIED IN OUR
STUDIES TO LEG LYMPHEDEMA AND
LIPEDEMA.
WE START WITH LEG BECAUSE WE
KNOW THE SOURCE OF LYMPH INSULT
DUE TO LYMPH REMOVAL IN THESE
CANCER CASES.
WE'VE ALREADY HEARD ABOUT BREAST
CANCER RELATED LYMPHEDEMA, BUT I
ALSO WANT TO POINT OUT THAT
GYNECOLOGICAL CANCER HAS A HIGH
INCIDENCE, MEANING 27 TO 41% OF
PATIENTS UNDERGOING TREATMENT
FOR GYNECOLOGICAL CANCER WILL GO
ON TO DEVELOP LYMPHEDEMA.
WHAT'S INTERESTING IS THAT NOT
ALL OF THESE PATIENTS DEVELOP
LYMPHEDEMA, RIGHT?
SO THAT'S WHY WE DO NEED THEE
PERSONALIZED RISK ASSESSMENT
MARKERS AND ALSO FOR THOSE
SUFFERING FROM LYMPHEDEMA LIKE
OUR PATIENT HERE, WE NEED TO
DEVELOP TOOLS TO OPTIMIZE THEIR
THERAPIES.
IN OUR PRELIMINARY STUDY WE SET
OUT TO TEST THE HYPOTHESIS THAT
IN LIMBS WITH LYMPH IMPAIRMENT
TISSUE SODIUM IS HIGHER COMPARED
TO CONTRALATERAL LIMBS.
WE ENROLLED NINE PATIENTS WITH
CANCER-RELATED LEG LYMPHEDEMA.
THEY UNDERWENT A PHYSICAL EXAM
TO CONFIRM THEIR LYMPHEDEMA
STAGE AND 3T MRI IN ORDER TO
QUANTIFY AND ANALYZE SODIUM IN
THE SKIN.
THE SUBCUTANEOUS ADIPOSE TISSUE
AND THE MUSCLE.
AND WHAT I'D LIKE TO DO NEXT IS
SHOW YOU A FEW CASE EXAMPLES AND
GROUP RESULTS.
LOWER EXTREMITY LYMPHEDEMA DUE
TO CANCER TREATMENT, SEVEN LYMPH
NODES REMOVED AND SHE'S ACTIVELY
MANAGED HER LYMPHEDEMA FOR 13
YEARS.
THE RIGHT LOWER EXTREMITY IS
QUITE LARGER THAN THE LEFT AND
THIS IS THE AFFECTED LEG ON THE
RIGHT.
NOW WE'RE GOING TO FOCUS ON THE
CALF REGION WITH CONVENTIONAL
MRI, THIS IS WATER-WEIGHTED
CONTRAST SO BRIGHT REGIONS OF
THE IMAGE HAVE MORE WATER AND WE
CAN OBSERVE ON THE AFFECTED
EXTREMITY THERE'S SKIN
THICKENING, SEUB CUTANEOUS
ADIPOSE TISSUE THICKENING AND AN
AREA OF DENSE TISSUE.
NEXT WHAT WE SEE ON SODIUM MRI,
THIS IS AGAIN OUR STANDARDIZED
IMAGE QUANTIFICATION, SO THIS
COLORIZED IMAGE WHERE YOU SEE
YELLOWS AND REDS CORRESPONDS TO
HIGHER TISSUE SODIUM.
AND YOU CAN SEE IN THE AFFECTED
LIMB THERE'S QUITE A BIT MORE
TISSUE SODIUM AND IT'S ALSO
LOCALIZED COMPARED TO THE
CONTRALATERAL LIMB THAT DID NOT
HAVE LYMPH NODE REMOVAL.
AND WHAT I LOVE ABOUT THIS CASE
EXAMPLE IS THE CONTRALATERAL
LIMB SERVES AS AN EXCELLENT
INTERNAL CONTROL.
WE KNOW THESE LEGS DID NOT
INGEST A DIFFERENT AMOUNT OF
SODIUM, BUT THE LEG AFFECTED BY
LYMPHEDEMA STORES MORE SODIUM
AND THAT'S REALLY WHAT WE MEAN
BY TISSUE SODIUM STORAGE, AND SO
WE WANT TO UNDERSTAND WHY THIS
HAPPENS, HOW IT OCCURS AND
PROGRESSES, AND WHO MIGHT BE AT
RISK FOR THIS TYPE OF
DEVELOPMENT.
SO NEXT I'LL SHOW TWO MORE CASE
EXAMPLES BECAUSE THIS ALSO
APPEARS TO BE STAGE-DEPENDENT.
SO IN THIS OBSERVATION, THIS IS
A PATIENT WITH STAGE I
LYMPHEDEMA.
ON SODIUM MRI IN THE AFFECTED
LIMB YOU CAN SEE THERE'S HIGHER
LEVELS OF THE REDS AND YELLOWS
SO HIGHER TISSUE SODIUM IN THE
IMPAIRED LIMB COMPARED TO THE
CAN TRA LATERAL LIMB WHICH IS IN
THE DASHED BOX.
MR LYMPHANGIOGRAPHY SHOWS EDEMA
IN THE AFFECTED LIMB.
IN ADVANCED STAGES WE'RE
STARTING TO OBSERVE AREAS OF
DENSE TISSUE ABOVE THE -- IN
MOST CASES ANTERIOR TO THE
MUSCLE AND THIS HAS RADIOLOGICAL
EVIDENCE OF FIBROSIS, WHERE WE
SEE THE HIGHEST AMOUNT OF SODIUM
DEPOSITION AND ALSO LYMPHEDEMA.
SO IN THIS PRELIMINARY STUDY,
SOME OF THE GROUP LEVEL RESULTS
ARE SHOWING TISSUE SODIUM
CONTENT IS ELEVATED IN THE SKIN
AS WELL AS SUBCUTANEOUS ADIPOSE
TISSUE IN LIMBS WITH LYMPHEDEMA
COMPARED TO THEIR CONTRALATERAL
LIMB, STAGE ZERO.
AND ALSO THAT TISSUE SODIUM
INCREASES WITH LYMPHEDEMA STAGE.
THIS EFFORT IS NOW FUNDED BY THE
NHLBI AND WE'RE PRETTY EXCITED
TO FOLLOW UP ON THESE
OBSERVATIONS IN A LARGER COHORT.
SO WE'RE ALSO INTERESTED IN A
DISEASE CALLED LIPEDEMA, AND
THIS IS A DISEASE WITH SUSPECTED
LYMPHATIC INVOLVEMENT THAT CAN
APPEAR SIMILAR TO LYMPHEDEMA.
IT ALSO APPEARS SIMILAR TO
OBESITY SO I'LL TRY TO WALK YOU
THROUGH SOME OF THE SYMPTOMS OF
AND HOW A CLINICIAN WOULD
DIFFERENTIATE LIPEDEMA.
SO YOU MIGHT OBSERVE ALL THESE
PHOTOS ARE FROM PATIENTS WITH
LIPEDEMA.
YOU MIGHT OBSERVE THEIR
EXTREMITIES ARE SWOLLEN AND THIS
CAN APPEAR SIMILAR TO LYMPHEDEMA
HOWEVER LIPEDEMA HAS BILATERAL
LEG SWELLING THAT STOPS AT THE
FEET.
SO YOU MIGHT ALSO OBSERVE THE
BODY CONTOURS ARE
DISPROPORTIONATE, AND THAT MIGHT
BE SIMILAR TO OBESITY, HOWEVER,
LIPEDEMA HAS MORE OF A GYNOID
FAT DISTRIBUTION AND LEG GIRTH
IS RESISTANT TO DIET, EXERCISE
OR BARIATRIC SURGERY AND THAT IS
DIFFERENT FROM OBESITY.
LIPEDEMA ALMOST EXCLUSIVELY
AFFECTS FEMALES, THE FAT IS
PAINFUL, EASY BRUISING AND
THERE'S A LOW PREVALENCE OF
DIABETES OR METABOLIC DISEASE
DESPITE HAVING HIGH BMI.
SO WHAT'S NEEDED IN THIS SPACE
CLINICALLY IS FOR AN OBJECTIVE
TOOL AND WAY TO DISTINGUISH
BETWEEN THESE DISEASES BECAUSE
IT HAS A VERY COMPLEX
DIFFERENTIAL DIAGNOSIS.
SO WE THINK IMAGING CAN PLAY A
PART IN THIS.
SO HERE'S WHOLE BODY IMAGING IN
A HEALTHY FEMALE COMPARED TO A
PATIENT WITH STAGE I LIPEDEMA.
THEY HAVE SIMILAR B PL. I.
THIS IS A FAT-WEIGHTED CONTRAST,
SO IF YOU START TO OBSERVE AT
THE WAIST YOU MAY SEE THAT THEY
HAVE A SIMILAR AMOUNT OF FAT
DEPOSITION BUT AS YOU SCAN DOWN
THROUGH THE LEGS AND FOLLOW
THESE ARROWS DOWN, YOU CAN
OBSERVE THERE'S GREATER FAT
DEPOSITION SUBCUTANEOUSLY IN THE
PATIENT WITH LIPEDEMA.
SO NOW FOCUSING ON THE CALF, I'M
SHOWING A FAT-WEIGHTED TISSUE
CONTRAST ON THE TOP IMAGE AND A
WATER-WEIGHTED ON THE BOTTOM.
HERE'S WHAT WE START TO OBSERVE
AND BEGIN TO QUANTIFY, THAT
THERE'S A FAT TO WATER VOLUME
RATIO ABOUT A LITTLE GREATER
THAN 1 OR ABOUT 1 IN THE PATIENT
WITH LIPEDEMA.
SO THAT MEANS AS MUCH FAT IS
SUPPORTED BY THE MUSCLE.
THIS IS THREE TIMES HIGHER FROM
A FEMALE WITH SIMILAR BMI.
HERE'S ANOTHER CASE EXAMPLE OF
ADVANCED STAGE III LIPEDEMA.
I'M SHOWING A CONTROL CASE
AGAINST LIPEDEMA CASE.
IN THE MIDDLE I'M SHOWING
FOREARM IMAGING AND ON THE
RIGHT, CALF LOWER EXTREMITY
IMAGING.
WHAT THIS STUDY HAS SHOWN US IS
THAT THERE'S A SIMILAR AMOUNT OF
FAT DEPOSITION IN THE UPPER
EXTREMITIES AS WELL AS SODIUM
CONTENT IN PATIENTS WITH
LIPEDEMA.
IN THE LOWER EXTREMITIES, IT'S
FULL OF SODIUM IN ALL THE
COMPARTMENTS WE'RE INTERESTED
IN.
SO HOW CAN WE USE THESE METRICS
TO MAYBE COMPARE AND
DIFFERENTIATE THESE DISEASES?
THE GRAPH ON THE LEFT IS SHOWING
LEG FAT FRACTION OR FAT TO WATER
RATIO.
IN THE CONTROL LIPEDEMA AND
LYMPHEDEMA PATIENTS.
ELEVATED FAT FRACTION HAS THE
LARGEST EFFECT SIZE IN LIPEDEMA.
THE GRAPH ON THE RIDE IS SHOWING
SKIN SODIUM IN THESE COHORTS.
WE SEE THE HIGHEST IN LYMPHEDEMA
BUT THERE'S ALSO A HIGHER AMOUNT
IN LIPEDEMA.
SO WE THINK TOGETHER THESE TOOLS
MIGHT BE USEFUL FOR
DIFFERENTIATING THESE CONDITIONS
AND IT ALSO TELLS US SOMETHING
ABOUT LIPEDEMA BECAUSE IT SHARES
SOME SIMILAR FEATURES TO LEG
LYMPHEDEMA.
SO I JUST WANT TO SHOW THIS
CONCEPT IN A REPRESENTATIVE CASE
EXAMPLE FINALLY THAT WHEN WE
COMBINE THESE IMAGING METHODS
TOGETHER, THIS MAY BE WHAT'S
REQUIRED TO REALLY START TO
PROFILE AND UNDERSTAND HOW
VASCULAR FUNCTION CAN IMPACT
TISSUE SODIUM AND FAT
COMPOSITION AND THERE MIGHT BE
OTHER METRICS OUT THERE THAT WE
CAN BEGIN TO LOOK AT.
BUT I THINK THESE ARE STARTING
TO SHOW -- THESE CASES ARE
STARTING TO SHOW SOME REALLY
INTERESTING THINGS ABOUT
VASCULAR FUNCTION IN THE LOWER
EXTREMITIES.
HERE ON MR LYMPHANGIOGRAPHY YOU
CAN SEE SORT OF AN INTERMEDIATE
LEVEL OF TISSUE VASCULARITY
COMPARED TO -- AND THAT ALSO
CORRESPONDS TO THEIR SODIUM
DEPOSITION IN THE LEG.
IN SUMMARY, THERE'S A CLINICAL
NEED FOR DEVELOPMENT OF
NONINVASIVE IMAGING OF LYMPHATIC
PHYSIOLOGY AND THIS CAN AID THE
DIAGNOSIS AND UNDERSTANDING OF
LYMPHEDEMA AND LIPEDEMA.
MRI TOOLS ARE WHAT I PRESENTED
TODAY, INCLUDING NONINVASIVE MR
LYMPHANGIOGRAPHY, ANATOMICAL AND
SODIUM MRI, AND THESE CAN BE
PERFORMED IN A CLINICALLY
FEASIBLE SCAN TIME AT 3 MINUTES
TOTAL.
OUR RESEARCH RESULTS WERE
PRELIMINARY BUT SHOWED US EDEMA
AND SODIUM ARE PRESENT IN LIMBS
WITH LYMPHEDEMA.
PRELIMINARY DATA INDICATES SKIN
SODIUM INCREASES WITH LYMPHEDEMA
STAGE AND SKIN AND SUBCUTANEOUS
ADIPOSE TISSUE AND LIPEDEMA
CONTAINS HIGH SODIUM CONTENT AND
EDIE MA.
IF YOU
EDEMA.
YOU CAN FOLLOW OUR LATEST
PUBLICATION IN JMRI.
I WANT TO END WITH SOME GAPS IN
CLINICAL IMAGING.
I WANT TO HIGHLIGHT THE
TRANSLATIONAL PATHWAY THAT
THERE'S A ROLE IN ALL PHASES OF
SCIENCE.
THEY NEED SOLUTIONS NOW AND THEY
NEED SOMETHING THEY CAN GET IN
THE CLINIC NOW.
I KNOW THERE'S SOME BEAUTIFUL
WORK WE CAN ALL DO AND WE CAN
IMPROVE UPON THE TECHNIQUES AND
TECHNOLOGIES BUT I THINK WE
REALLY SHOULD BE LOOKING OUT FOR
THOSE TECHNIQUES THAT CAN BE
APPLIED IN THE CLIN CLICK ANE
LATER PHASES OF TRANSLATION.
MY STUDY FALLS AROUND T1, MAYBE
T2, AND I THINK THERE'S SOME
REALLY EXCITING OPPORTUNITIES
THAT ARE OUT THERE.
FOR INSTANCE, THERE'S SOME
LYMPHATIC THERAPIES THAT ARE
BEING INVESTIGATED AND WE'VE
ALREADY HEARD ABOUT SOME OF
THESE TODAY FROM OUR SURGICAL
TEAMS.
IN OUR STUDY, WE'RE EVALUATING
STANDARD OF CARE PHYSICAL
THERAPY BECAUSE WE THINK THIS
CAN HELP DEMONSTRATE AND
VALIDATE THE NOVEL IMAGING
METHODS THAT WE'VE BEEN
OBSERVING IN CROSS-SECTIONAL
STUDY DESIGNS.
IN THIS CASE I'M SHOWING LYMPH
ANGIOCHANGES PRE AND POST -- BUT
THERE'S ALSO SOME EXCITING FARM
PHARMACEUTICAL AND SURGICAL
THERAPIES BEING DEVELOPED FOR
LYMPHEDEMA AND I THINK
TECHNOLOGY CAN PLAY A ROLE IN
EVALUATING THOSE.
I'D LIKE TO ACKNOWLEDGE MY
COLLEAGUES AND COLLABORATORS,
THE AMERICAN HEART ASSOCIATION,
THE LIPEDEMA FOUNDATION AND THE
NHI FOR SUPPORTING THIS WORK.
IF YOU WANT TO WORK WITH US IN
ANY WAY, PLEASE REACH OUT TO ME
OR THE LAB BY EMAILING US,
>> AWESOME.
THANK YOU, RACHELLE.
THAT WAS BEAUTIFUL WORK.
I ALWAYS ENJOY HEARING YOUR
PROGRESS AS WELL, SO
CONGRATULATIONS ON THAT.
SO AGAIN, WE WILL TAKE QUESTIONS
WITH YOU AND THE GROUP AT THE
END, SO NOW IT'S MY PLEASURE TO
INTRODUCE OUR NEXT SPEAKER, MARK
NICOLLS, WHO IS AT STANFORD
UNIVERSITY SCHOOL OF MEDICINE
AND HE'LL BE TALKING TO US ABOUT
THE PATHWAYS OF INJURY AND
REPAIR IN LYMPHEDEMA.
THE FLOOR IS YOURS.
>> THANK YOU.
CAN YOU HEAR ME?
>> YEP, WE CAN HEAR YOU WELL.
THANK YOU.
>> THANK YOU VERY MUCH, TIM AND
THE ORGANIZERS OF THIS
CONFERENCE.
SO WHAT I'LL BE TALKING ABOUT
TODAY IS LYMPHEDEMA AS A
PARADIGM FOR EVALUATING
LYMPHATIC DYSFUNCTION.
AND WE HEARD A PREVIEW OF SOME
OF THE THINGS I'M GOING TO TALK
ABOUT TODAY AS DR. ROCKSON GAVE
IN THE KEYNOTE ADDRESS A TRIAL
THAT WAS INVOLVING -- TARGETING
5-LIPOXGENASE IN LYMPHEDEMA AND
WE'LL RETREAD SOME OF THE GROUND
THAT DR. ROCKSON TALKED ABOUT
BUT FLESH OUT SOME OF THE
SCIENTIFIC DETAILS A LITTLE BIT
MORE.
THEN WE'LL GET INTO SOME NEWER
BIOLOGY ABOUT HOW HIF MIGHT BE
CONTRIBUTING TO LYMPHATIC REPAIR
AND LYMPHATIC HEALTH.
WE'LL ALSO BRIEFLY TALK ABOUT
NEW RESEARCH NOW BEING PUBLISHED
ON SPHINGOSINE SIGNALING AND
LYMPHATICS.
SO I WAS ASKED TO REALLY TALK
ABOUT HOW INFLAMMATION MAY BE
AFFECTING THE EVOLUTION OF
LYMPHEDEMA.
WE KNOW THAT WITH THE
PATHOPHYSIOLOGY OF ACQUIRED
LYMPHEDEMA, LYMPHATIC INJURY CAN
BE CAUSED BY SURGERY, RADIATION
AND OBESITY, AND WE'VE HEARD
ABOUT SOME OF THOSE FACTORS IN
THIS SESSION.
WE KNOW TH1, TH2 AND TH17 ALONG
WITH ACTIVATED MACROPHAGES AND
NEUTROPHILS CAN BE PRESENT AND
LIKELY HARMFUL IN THIS
CONDITION.
OUR GROUP HELPED CHARACTERIZE
LEUKO -- THERE'S ALSO
INSUFFICIENT REPARATIVE IMMUNE
RESPONSES WITH T REG ACTIVITY
AND MACROPHAGES AS WELL AS
INSUFFICIENT REPARATIVE FACTOR
PRODUCTION, NOTELY, VEGF C.
ALL OF THIS RESULTS IN A LOSS OF
SMOOTH MUSCLE SELL COVERAGE,
FLUID RETENTION, FIBROSIS, AND
ADIPOSE DEPOSITION.
SO I'M NOT GOING TO BELABOR THIS
STUDY TOO MUCH, WHICH STAN
DESCRIBED THIS MORNING.
SUFFICE TO SAY THERE WAS A
RATIONALE FOR TARGETING
INFLAMMATION IN LYMPHEDEMA, AND
THIS LED TO USING KETOPROFEN,
WHICH IS AN NSAID WITH DUAL
ANTI-INFLAMMATORY MECHANISM, BUT
IT HAS SOME UNTOWARD PROPERTIES
WHICH MAKE US NOT WANT TO USE IT
CLINICALLY FOR LONG TERM.
WE KNOW THAT IT INHIBITS
5-LIPOXYGENASE AND COX2, WE
DIDN'T REALLY KNOW WHY
5-LIPOXYGENASE WAS HELPING, WHY
WE'RE TARGETING 5-LO WOULD BE
HELPFUL AND IS THAT THE REASON
WHY KETO WAS WORKING.
THIS IS A NICE REVEUL THAT JIANG
IN MY LAB WITH AN R01 FOCUSING
ON LYMPHEDEMA SHOWS HOW NUCLEAR
5-LO CAN GET PHOSPHORYLATED
TRANSIENTLY LEAD TO LTA4 AND
THEN DEPENDING ON WHERE THE
ENZYME IS ACTIVATED, CAN EITHER
GENERATE -- ASSOCIATED WITH
BRONCHOCONSTRICTION AND A
VARIETY OF OTHER PARAMETERS AS
WELL AS LTB4, WHICH CAN BIND TO
ITS RECEPTORS, MAINLY BLT1, BUT
ALSO BL T2.
THIS HAS BEEN ASSOCIATED WITH A
VARIETY OF CONDITIONS, BUT WHAT
WE HAD DISCOVERED SEVERAL YEARS
PRIOR LOOKING AT PULMONARY
HYPERTENSION RESEARCH IS THAT
LTB4 CAUSES ENDOTHELIAL
APOPTOSIS AND TRANSFORMATION.
WE GOT PAIRED UP WITH STAN
ROCKSON RIGHT AROUND 2010, 2011,
TO TRY AND EXPLORE THESE
PATHWAYS EVEN AS THE KETOPROFEN
TRIAL WAS BEGINNING TO OCCUR.
AND TO STUDY LYMPHEDEMA, LET ME
JUST BRIEFLY REVIEW THE TAIL
MODEL, WHERE WE CAN EITHER DO A
SHAM SURGERY WITH A SURFACE NICK
OF THE TAIL, OR WE CAN CUT THE
LYMPHATIC TRUNKS ON BOTH SIDES,
AND THIS LEADS TO A STEREO TYPIC
INCREASE IN THE GIRTH OF THE
TAIL THAT MIMICS LYMPHEDEMA MUCH
IN THE WAY THAT DR. ROCKSON
DESCRIBED.
NOW IT'S AN INTERESTING MODEL
BECAUSE YOU DO GET THIS RISE IN
TAIL VOLUME WHICH OCCURS, THEN
YOU GET A SLIGHT TAPERING THAT
OCCURS OVER TIME, BUT THE
ANIMALS DON'T GENERALLY
COMPLETELY RESOLVE.
SO IT'S A GOOD MODEL TO STUDY
LYMPHEDEMA THAT MIGHT BE
RELEVANT TO THE CLINICAL
CONDITION.
SO WE INTERROGATED THIS MODEL
USING A VARIETY OF APPROACHES.
IF WE USE IBUPROFEN WHICH JUST
TARGETS COX1, COX2, WE SAW NO
BENEFIT TO THE TREATMENT.
BUT IF WE USED KETOPROFEN JUST
LIKE THE HUMAN CONDITION WHICH
BLOCKS BOTH COX-1 AND COX-2 AS A
DUAL INHIBITOR, IT WAS
EFFECTIVE.
AS WAS SIE. ILEUTON BUT WHEN YOU
BLOCK THE CYSLTs, IT WAS NOT
EFFECTIVE.
IF WE USED -- WHICH BLOCK THE
LTB4, WE SAW EFFECTIVE TREAT M
OF THE DISEASE.
SO WHAT DOES THIS LOOK LIKE?
IN OUR LYMPHEDEMA TAIL MODEL,
WHAT YOU CAN SEE IS THIS
INCREASED INTERSTITIAL FLUID,
DERMAL THICKENING, AND IF YOU
TREAT WITH AN LTB4 ANTAGONIST,
YOU SEE YOU CAN HELP PREVENT
THIS, AND IT LOOKS CLOSE TO THE
SHAM.
NOW, WE CAN INJECT EVANS BLUE TO
GAUGE HOW WELL IT'S TAKEN UP AND
SHOW IN A SALINE-TREATED
LYMPHATIC SURGERY MODEL, YOU
DON'T GET GOOD RESORPTION DISTAL
TO WHERE THE LYMPHATIC TRUNKS
HAVE BEEN CUT.
BUT IN AN ANIMAL WHERE YOU'VE
TREATED WITH LEUKOTRIENE B4, YOU
SEE THIS SUGGESTING IT MIGHT BE
AN IMPACTFUL TREATMENT.
SO I'M GOING TO DO A SLIGHT
DETOUR HERE JUST TO TALK ABOUT
WHY WE DO SCIENCE AND WE'RE NOT
ALWAYS RIGHT WITH OUR
HYPOTHESES, BUT IT CAN LEAD TO
INTERESTING DISCOVERIES.
SO WE FOUND -- YOU MIGHT EX-MECT
GIVEN OUR DISCOVERIES THAT IF
YOU USE A 5-LO OR LTB KNOCKOUT
PLOWS THEY WOULD BE PROTECTED
FROM LYMPHEDEMA, YOU'RE
ESSENTIALLY BLOCKING LTB4 AT A
MORE ABSOLUTE LEVEL.
INSTEAD, WE FOUND IN A COMPLETE
ABSENCE OF NORMAL LTB4 SIGNALING
THE TAILS BECAME EDEMATOUS AND
NECROTIC.
SOME OF THEM EVEN FELL OFF.
WHICH SUGGESTED TO US THAT
SOMEHOW INHIBITING LTB4 A FEW
DAYS AFTER SURGERY WAS DIFFERENT
IN THE COMPLETE ABSENCE OF LTB4.
AND SO WHAT WE FOUND IN VITRO
WAS THAT AT PHYSIOLOGIC
CONCENTRATIONS OF 5 TO 10
NANOMOLAR, LTB4 IS ACTUALLY PRO
LYMPHANGIOGENIC, WHEREAS WHEN
YOU GET INTO THE TOXIC REGIONS
THAT BUILD UP OVER TIME, LTB4 IS
HARMFUL, AND BLOCKS NORMAL
LYMPHATIC ENDOTHELIAL CELL
FUNCTION AND CAN CAUSE
ENDOTHELIAL CELL DEATH, MUCH
LIKE WE SEE IN PULMONARY
ENDOTHELIAL CELLS.
SO ALL OF THIS WORK LED TO TWO
CLINICAL TRIALS, ONE WHICH IS
ALREADY BEING PERFORMED.
THE ONE STAN DESCRIBED WAS
UNDERPOWERED, BUT WE HAD SOME
ANECDOTAL COMPELLING RESPONSES
WHICH PROMPTED A NEW TRIAL THAT
WAS MORE LIMITED BUT A LARGER
GROUP OF PATIENTS AND MORE
FOCUSED AND CONDUCTED AT
STANFORD, WHICH STAN IS LEADING.
SO EVEN AS WE'RE EVALUATING
THESE INFLAMMATORY PATHWAYS, OUR
GROUP IS ALSO INTERESTED IN
HYPOXIC SIGNALING, AND WE KNOW
THAT IT'S IMPORTANT IN DRIVING
ANGIOGENESIS VIA TRANSCRIPTION
FACTORS KNOWN AS THE HYPOXIA
INDUCIBLE FACTORS, OR HIFs.
WE WONDERED WHETHER OR NOT THE
HIFs ARE IMPORTANT IN
LYMPHATIC REPAIR.
SO AGAIN, XINGUA JIANG IN OUR
LAB CONDUCTED THESE STUDIES AND
SURPRISINGLY WE SAW IN HUMAN
LYMPHEDEMA SKIN WE SEE A
RELATIVELY INCREASED AMOUNT
LINING ENDOTHELIAL CELLS BUT A
DECREASED AMOUNT OF HIF2 ALPHA.
WE KNEW THAT HIF2 ALPHA WAS ALSO
AN IMPORTANT SURVIVAL FACTOR IN
PULMONARY ENDOTHELIAL CELLS.
SO WE QUESTIONED WHETHER OR NOT
THIS COULD HAVE A ROLE IN WHY
PATIENTS DEVELOPED AND
PROPAGATED THEIR LYMPHEDEMA.
NOW IF WE USE THE MOUSE TAIL
MODEL WHICH I'VE ALREADY
DESCRIBED TO YOU WHERE YOU GET
THIS INCREASE AT ABOUT TWO WEEKS
AND GRA ACTUAL RESOLUTION, IF WE
USE THAT MODEL, WE INDEED FIND
THAT YOU GET INCREASED AMOUNTS
RELATIVELY OF HIV-1 ALPHA IN THE
LYMPHATICS BUT YOU SEE -- IN THE
ADVANCED LYMPHEDEMA TAIL.
THE TAIL MODEL AGAIN SEEMS TO
REPLICATE THE HUMAN CONDITION.
SO THE NEXT THING WE DID WAS TO
DEVELOP A GENETIC KNOCKOUT OF
LYMPHATIC ENDOTHELIAL CELL
HIF2 ALPHA, AND WE ALSO
DEVELOPED THESE WITH HIF1 ALPHA.
WE ALSO DEVELOPED OVEREXPRESSING
HIF1 AND HIF2 ALPHA BUT I WON'T
BE PRESENTING THAT DATA TODAY.
AND WE DEVELOPED THESE BY
CROSSING PROX1-CRE ER T2 WITH
HIF 1 AND HIF 2 TRANS GENE.
AT A DAY WHEN WE NORMALLY WOULD
EXPECT A GROWTH OF THE
LYMPHATICS TOWARD EACH OTHER AT
THE DORSAL MIDLINE.
WHAT WE SEE IS THESE EMBRYOS AT
DAY E16.5 HAVE DORSAL EDEMA,
WHICH CAN BE INDICATIVE OF -- OR
IS A REPLICATE FOR LYMPHEDEMA,
AND A FAILURE TO CLOSE THIS
MIDLINE LYMPHATIC VESSEL FUSION,
SUGGESTING THAT LYMPHATIC
ENDOTHELIAL HIF 2 ALPHA IS
IMPORTANT FOR DERMAL LYMPHATIC
DEVELOPMENT.
IF YOU EVALUATE THESE ANIMALS 2N
INJECTION, WHAT YOU FIND IS THE
EVANS BLUE DYE IS TAKEN UP
NORMALLY AND RESORBED IN THE
WILD TYPE ANIMAL COMPARED TO THE
ENDOTHELIAL KNOCKOUT, LYMPHATIC
ENDOTHELIAL KNOCKOUT HIF
2 ANIMAL, AGAIN SUGGESTING THAT
THESE DEFICIENCIES CARRY ON INTO
LIFE, POSTNATAL LIFE.
OKAY.
SO BAYICALLY WHAT WE BE
IS HIF 2 DEFICIENCY CAUSES
LYMPHATIC DYSFUNCTION IN THESE
ANIMALS, AND THEY DEVELOP
INCREASED TAIL LYMPHEDEMA, AND
THIS BRIEFLY SUMMARIZES OUR
EXPERIENCE.
INTERESTINGLY, WE CAN REPLICATE
AND RESCUE THESE ANIMALS FROM
DEVELOPING LYMPHEDEMA BY GIVING
ADENOTHERAPY, WHICH INCREASES
ANGIOPOIETIN EXPRESSION.
I'LL BRIEFLY MENTION WE'RE NOW
STUDYING SPHINGOCINE SIGNALING,
SHOWING THAT S1P AND S1P
METABOLITES ARE DECREASED IN
LYMPHATIC ENDOTHELIAL CELLS.
AND THIS IS THE WORK OF OUR
LABORATORY.
WE'VE ALSO GENERATED THESE MICE
THAT ARE DEFICIENT IN
S1PR1 SIGNALING AND SHOW THAT IN
THE ABSENCE OF NORMAL S1P
SIGNALING, WE GET AN
EXACERBATION OF LYMPHEDEMA.
WE FINALLY ATTRIBUTE THIS TO A
DEFECT IN THE NORMAL -- BRINGING
IN OF T-CELLS INTO THE
LYMPHATICS WITH ACTIVATION OF
T-CELLS, AND I DON'T REALLY HAVE
TIME TO SHOW THIS TO YOU TODAY.
SO IN CONCLUSION, THE LYMPHATIC
CIRCULATION HAS A VARIETY OF
UNIQUE FUNCTIONS THAT ARE
RELATIVELY UNDERSTUDIED, AND WE
NEED OBVIOUSLY DRUG TARGETS.
THERE ARE KEY SIGNALING PATHWAYS
THAT ARE EMERGING WHICH INCLUDE
HIF 2 ALPHA AND S1P.
IT'S EVIDENT THAT LYMPHATIC
VASCULATURE REGULATES T-CELL
ACTIVATION.
SO IT'S NOT JUST -- THE
LYMPHATICS ARE IMPORTANT IN THE
VESSEL FORCE FOR ACTIVATING N
T-CELLS.
WE NEED TO THINK WE NEED TOT
EVALUATING THESE PATHWAYS OF
INJURY AND REPAIR SO WE CAN MORE
COMPLETELY UNDERSTAND THIS SO WE
CAN DEVELOP ORAL DRUGS.
SO WE NEED TO INTEGRATE THESE
PATHWAYS.
WE NEED TO BETTER UNDERSTAND THE
TRANSCRIPTIONAL MACHINERY OF
LYMPHANGIOGENIC PATHWAYS AND
CHARACTERIZE THE ROLE OF
LYMPHATIC VASCULATURE IN IMMUNE
ACTIVATION.
AND FINALLY, WE NEED TO DEVELOP
THERAPEUTIC LYMPHANGIOGENESIS
CONCEPTS, IN SOLID ORGAN
TRANSPLANTS, WHICH WE'RE
INVESTIGATING, AND IN BREAST
CANCER PATIENTS, WE'VE HEARD
ABOUT ELEGANT LYMPH NODE
TRANSPLANT THERAPIES TODAY.
CAN WE PREEMPTIVELY TARGET THESE
PATIENTS SO THEY DON'T DEVELOP
LYMPHEDEMA?
I REALLY WANT TO HIGHLIGHT AMY,
XINGUA, DONGEON, RHINE AND LAN
AND OUR COLLABORATIONS WITH
DR. ROCKSON.
>> THANK YOU FOR YOUR BEAUTIFUL
TALK, NICE SECTION ON EACH OF
THESE MECHANISMS.
OUR NEXT SPEAKER IS RAGHU
KATARU, SPEAKING ABOUT
MECHANISMS OF FIBROSIS AND
LYMPHATIC DYSFUNCTION IN
SECONDARY LYMPHEDEMA.
RAGHU, THE FLOOR IS YOURS.
>> I HOPE YOU GUYS CAN HEAR ME
PROPERLY, RIGHT?
>> YES, WE CAN.
>> AND THE SLIDES ARE GOOD.
OKAY.
>> YEP.
>> THANK YOU, TIM.
THANK YOU FOR THE INTRODUCTION.
IT'S REALLY AN HONOR TO BE HERE
TO SHOW AND SHARE SOME OF OUR
LATEST DATA RELATED TO SECONDARY
LYMPHEDEMA.
THIS TALK IS MORE ABOUT A COUPLE
OF FIBROSIS, A BIT LESS
ABOUT --, PER SE.
I WANT TO SAY ALL THE DATA
THAT'S GOING TO BE SHOWN IN THIS
TALK IS ACTUALLY UNPUBLISHED,
UNSUBMITTED OR READY TO BE
SUBMITTED.
SO I'M HAPPY TO SHARE AND GET
SOME FEEDBACK FROM YOU GUYS.
SO LYMPHEDEMA DOESN'T REQUIRE AN
INTRODUCTION HERE ANYMORE,
THANKS TO ALL THE SPEAKERS
EARLIER.
BUT ANYHOW, I WOULD LIKE TO GIVE
A COUPLE -- THE PATHOPHYSIOLOGY
OF LYMPHEDEMA IS VERY COMPLEX,
WHERE THE PATHOPHYSIOLOGY
DISEASE IS CHARACTERIZED BY
CHRONIC INFLAMMATION AND
FIBROSIS THAT ACTUALLY AFFECTS
LYMPH STRUCTURE AND FUNCTION,
THE LYMPHATICS -- CAN AFFECT
INFLAMMATION AND FIBROSIS.
SO THESE TWO COMPONENTS GO HAND
IN HAND.
IN TERMS OF OVER THE PAST 10
YEARS OR SO, OUR LAB HAS BEEN
FOCUSING ON THE UNDERSTANDING OF
INFLAMMATORY REACTIONS THAT
OCCUR IN LYMPHEDEMA, AND WE
FOUND THAT CD4 POSITIVE CELLS
THAT ARE ACTUALLY TH2 TYPE
DIFFERENTIATED PLAY A CRITICAL
ROLE IN THE PATHOLOGY OF THE
DISEASE.
SO OUR RESEARCH -- A QUICK RECAP
OF WHAT WE HAVE DONE FOR THE
LAST YEARS IS T-CELL
PROLIFERATION BY TACROLIM UCHT S
ARE MAYBE BLOCKING BY IL4 AND
IL13 MONOCLONAL ANTIBODY
TREATMENT, BLOCKING -- TO
INHIBIT FIBROSIS, ROANTLY WE REE
PUBLISHED THIS PAPER.
THESE ARE SOME OF THE METHODS
WHERE WE SHOWED THERE WAS A
POSITIVE WAY YOU CAN ACTUALLY
PREVENT LYMPHEDEMA BY THESE
METHODS.
SO IN THIS PROCESS, WHAT WE CAME
ACROSS IN OUR RECENT DATA, THE
ONE PHENOTYPE WHICH PROMINENTLY
SHOWED UP IS STRONG UPREGULATION
OF KERATINS FROM HUMAN SAMPLES
WHICH WE HAVE PERFORMED RNA SEQ
ON.
SO AS YOU CAN SEE THE NUMBER
HIGHLY UPREGULATED.
THIS LED US TO THINK THAT MAYBE
THE KERATIN SIGNATURE SUGGESTS
THERE'S A -- IN THE PATHOLOGY.
SO THIS LED US TO THINK A LITTLE
DEEPER INTO THIS AND SO THESE
ARE SOME OF THE HISTOLOGY
IMAGES, THE NORMAL IS NORMAL
ARM, LYMPHEDEMA IS THE
LYMPHEDEMA ARM OF THE SAME
PATIENT.
SHOWING THAT YOU CAN CLEARLY SEE
THAT THERE IS A HYPERKERATOSIS
AND THICKENED EPIDERMIS IN THE
LYMPHEDEMA INDICATING THERE IS
DEFINITELY HYPERKERATOSIS
HAPPENING, BUT THE QUESTION WE
HAD WAS HOW IT CONTRIBUTES TO
LYMPHEDEMA PATHOLOGY.
TO UNDERSTAND THAT WHEN WE DID
THE RESEARCH, KERATIN KERATN
DERMATITIS WHICH IS WELL
STUDIED, THERE'S A STRONG --
PLAY AN IMPORTANT ROLE IN THAT.
SO CONSIDERING THIS, WE THOUGHT
LYMPHEDEMA BEING A SKIN DISEASE,
THAT'S WHAT AT LEAST WE BELIEVE,
AND THEN WE THOUGHT MAYBE, YOU
KNOW, THERE IS A POSSIBILITY
THAT KERATINOCYTES PLAY SOME
ROLE IN THE LYMPHEDEMA TOO.
SO TO UNDERSTAND THAT, THIS IS A
HUMAN DATA WHERE WE GOT SAMPLES
FROM A HUMAN LYMPHEDEMA
PATIENTS, BIOPSY SAMPLES WHERE
WE DID HISTOLOGY AND --
INITIALLY TO UNDERSTAND THE
HYPERKERATOSIS.
AS YOU CAN SEE, THERE'S A
SIGNIFICANT HYPERKERATOSIS IN
THE LYMPHEDEMA PATIENT'S SKIN.
INTERESTINGLY, THERE IS AN
UPREGULATED -- THE PROLIFERATION
OF EPIDERMAL CELLS,
KERATINOCYTES IS VERY HIGH -- IN
HEALTHY SKIN IS HIGHLY
UPREGULATED AND ALSO KERATIN 14
WHICH IS A MARKER OF VESSEL CELL
LAYER IS ACTUALLY PRESENTED
THROUGHOUT THE WHOLE EPIDERMIS,
INDICATING OR SUPPORTING OUR RNA
SEQ DATA FOR EXPRESS OF
KERATINS, AND THESE THINGS ARE
QUANTIFIED BY WESTERN BLOTTING,
PCR AND OTHER METHODS.
SO THE NEXT THING IS, OKAY, WE
SEE A HYPERPLASTIC EPIDERMIS, SO
WHAT ARE THEY DOING.
WE STAINED FOR TH2-INDUCING
CYTOKINES LIKE KLK5, PAR2, TSLP,
IL-33, LYMPHEDEMA SEEMS TO BE --
IN CASE OF LYMPHEDEMA, THESE THY
UPREGULATED.
AGAIN, THIS IS QUANTIFIED BY
OTHER METHODS LIKE WESTERN
BLOTTING AND PCR, JUST TO
COLLABORATE OUR -- OF THE DATA.
SO CONSIDERING THESE CHANGES IN
THE HUMAN HYPERKERATOSIS IN THE
HUMAN LYMPHEDEMA SKIN, WE WANTED
TO SEE WHETHER MOUSE ACTUALLY
FOLLOWS THE SAME WAY, SO WE
USED -- I KNOW MOST YOU HAVE
KNOW THIS MODEL OF TAIL
LYMPHEDEMA, BUT JUST FOR SOME
PEOPLE WHO ARE NOT AWARE OF
THIS, THE DALE TAIL LYMPHEDEL
WE'RE SHOWING HERE IS WHERE WE
SURGICALLY REMOVE -- SUPERVISOR
PICIAL AND -- LYMPHATICS, AND AT
FOUR TO SIX WEEKS, YOU CAN SEE
DEVELOPMENT OF LYMPHEDEMA.
THIS IS ONE OF THE MOST COMMONLY
USED METHOD, MODEL FOR --
MODELS.
SO OUR TAIL LYMPHEDEMA MODEL
ALSO SHOWED INCREASED
HYPERKERATOSIS, INCREASE IN
PROLIFERATION OF EPIDERMAL
CELLS, INCREASE OF KERATIN 6 AND
KERATIN 14 EXPRESSION AS EARLY
AS TWO WEEKS.
THIS DATA IS ACTUALLY SIX WEEKS
DATA, I'M GOING TO SHOW YOU TWO
WEEKS DATA LATER ON, AND THE
QUANTIFICATION FOR THAT.
AND AGAIN, SIMILAR TO HEUL MAN
DATA, YOU CAN SEE THE
HYPERPLASTIC EPIDERMIS IS A
SOURCE OF TH2-INDUCING
CYTOKINES, THIS INDUCE FIBROSIS
LIKE -- AND THE QUANTIFICATION
IS DONE BASED ON RNA SEQ, PCR
AND WESTERN BLOTTING FROM THE
MOUSE TISSUE AS WELL.
SO THE SUMMARY UNTIL THEN WAS
THAT BOTH -- WE CAN SEE
HYPERKERATOSIS BOTH IN HUMAN AND
MOUSE -- FROM EARLY STAGES.
AS YOU CAN SEE HERE, WE WANTED
TO SEE -- SINCE WE SEE A
TH2 SIGNATURE, I WANTED TO SEE
WHETHER TH2 SIGNATURE PRECEDES
OUR -- HYPERKERATOSIS.
AT TWO WEEKS TIME YOU CAN SEE
HYPERKERATOSIS IN THE TAIL
MODEL.
WE DON'T SEE A LOT OF --
INFORMATION YET.
BUT BY SIX WEEKS, HYPERKERATOSIS
IS HIGHLY PROMINENT, THE TISSUE
INFLAMMATION ALSO STARTS TO SHOW
UP INDICATING THAT ACTUALLY THE
HYPERKERATOSIS PRECEDES T-CELL
INVOLVEMENT, T-CELL INFILTRATION
AND T-CELL INFLAMMATION, SOME OF
THE QUANTIFICATIONS ARE THE
SAME.
SO THE NEXT QUESTION IS WHAT
ASPECT OF LYMPHATIC INJURY
ACTIVATES KERATINOCYTES WHEN
PROLIFERATING THEM.
SO WE THOUGHT MAYBE THE FLUID
ACCUMULATING IN THE INTERSTITIAL
SPACES MIGHT HAVE SOMETHING TO
DO.
SO WE HAD OPPORTUNITY TO COLLECT
LYMPHEDEMA FLUID FROM PATIENTS'
ARM AND WHEN THIS FLUID CULTURED
WITH HUMAN KERATIN SITES IN
VITRO, WHEN COCULTURED WITH
FLUID, YOU CAN SEE PROLIFERATION
OF KERATINOCYTES -- JUST LIKE
THE WAY WE HAVE SEEN IN VIVO,
AND I'M NOT BRINGING ALL THE
QUANTIFICATIONS HERE TO MAKE IT
SHORTEN AND CRISP.
SO
WE WANTED TO SEE DOES
INHIBITING PROLIFERATION OF
KERATINOCYTES RESCUES LYMPHEDEMA
PHENOTYPE?
TEAR FLEUN MIGHT ACTS BY
FILTRATING -- INHIBITING CELL
PROLIFERATION.
IT LOOKS LIKE TERIFLUNOMIDE
SIGNIFICANTLY REDUCED THE TAIL
VOLUME AS WE CAN SEE BY THE
QUANITIFICATIONS, AND THE
REDUCTION OF HAIRP HYPERKERA,
SOME EFFECTS ARE QUANTIFIED
HERE.
SO WE WENT AHEAD AND CHECKED
WHETHER IT REDUCES NOT ONLY
HYPERKERATOSIS BUT ALSO REDUCES
THE PROLIFERATION OF
KERATINOCYTES, THEIR EXPRESSION
OF KERATIN 6 AND OTHER KERATIN
PROTEINS, AND THEIR EXPRESSION
OF TSLP, IL-33, OTHER --
INDUCING CYTOKINES.
SO THE TAKE-HOME MESSAGE IS THAT
IN SUMMARY, IF I WANT TO
SUMMARIZE THIS PART, THERE IS
LYMPHATIC INJURY AND THEN
THERE'S INFLAMMATORY CYTOKINES
AND PROTEASES AND LYMPHATIC
FLUID, THEY COME IN TOUCH, THEY
GET ACTIVATED, THERE IS
PROLIFERATION OF HYPERKERATOSIS
AND THERE IS DSLP AND IL-33 AND
OTHER -- CYTOKINES THAT ACTUALLY
CAN HELP DIFFERENTIATION OF
TH2 CELLS AND THEN HELPING
FIBROSIS AND DAMAGE TO LECs
WHICH WE HAVE SHOWN BEFORE.
SO THIS IS ONE MECHANISM WHERE
POTENTIALLY KERATINOCYTES IN
LYMPHEDEMA CONTRIBUTE TO THE
PATHOLOGY OF LYMPHEDEMA FIBROSIS
AND MAYBE INDIRECTLY --
DYSFUNCTION.
HOW ELSE HYPERKERATOSIS
CONTRIBUTES TO FIBROSIS IN
LYMPHEDEMA?
IN DOING THIS WORK, WE NOTICED
THE KERATINOCYTES, THIS IS AGAIN
HUMAN DATA, THE HUMAN LYMPHEDEMA
SKIN ACTUALLY HAS SIGNIFICANT
HYPERKERATOSIS AND RETE RIDGE
FORMATION, THESE PROJECTIONS OF
THE SKIN, AND THE CELLS IN THE
BASAL LAYER OF EPIDERMIS SEEMS
TO BE USING THEIR -- POLARITY AS
SHOWN IN THESE HIGH
MAGNIFICATION IMAGES.
OF COURSE THERE IS A SUBDERMAL
POSITION, AND MORE IMPORTANTLY,
WE SEE A LOT OF VIMENTIN
POSITIVE CELLS, SO THIS LED US
TO THINK WHETHER IS THERE ANY
POSSIBILITY OF EMT HAPPENING IN
LYMPHEDEMA.
EMT IS A PHYSIOLOGICAL PROCESS
WHERE THE EPITHELIAL CELLS ARE
TRANSITIONED INTO MESENCHYMAL
CELLS.
BY LOSING -- MARKERS AND
GAINING -- MARKERS, IT'S SEEN IN
WOUND HEALING AND CANCER -- WHAT
WE NOTICE IS A LOT OF THESE IN
THE BASAL LAYER DON'T EXPRESS
EPIDERMAL MARKERS OR THEY'RE
LOSING EPIDERMAL MARKERS IN
HUMAN PATIENT DATA AS WE CAN SEE
FROM THESE IMAGES.
THE OTHER EMT INDICATOR IS GAIN
OF EMT MARKERS ARE MESENCHYMAL
MARKERS.
AGAIN, YOU CAN SEE FSP1, MMP9,
SLUG, ITGB4 AND OTHER
MESENCHYMAL MARKERS EXPRESSED BY
THESE BASAL LAYER CELLS,
INDICATING THERE IS EMT
HAPPENING.
THE THIRD ONE IS INDIVIDUAL AND
CELL MIGRATION.
YOU CAN SEE PROJECTIONS AND
PROTRUSIONS, TRYING TO CROSS THE
BASAL CELL MEMBRANE.
SO THESE THREE INDICATIONS ARE
ALSO INDICATORS OF EMT ALSO
OBSERVED IN TAIL MODEL OF MOUSE,
NOT JUST IN HUMANS.
WHICH WE SHOWED HERE BY --
QUANTIFIED BY WESTERN BLOTTING
AND A COUPLE OF OTHER METHODS.
SO WE WANTED TO SHOW WHETHER --
WITH TRANSFERRED THE
KERATINOCYTES BY USING MOUSE.
YOU CAN ACTUALLY SEE -- BY SIX
WEEKS, THERE IS SO MUCH OF -- IN
THE EPIDERMAL LAYER
INDICATING -- AND THEN SOME OF
THE VIMETIN -- UNDERGOING EMT.
SOME OF THE CELLS IN THE DERMIS
HAVE ALREADY MIGRATED.
SO SOME OF THIS EVIDENCE CLEARLY
SHOWS THERE IS EMT HAPPENING,
THEN WE CHARACTERIZE
KERATINOCYTES IN THE FLUID, THEY
EXPRESS VIMENTIN AND OTHER
MARKERS, EMT MARKERS.
THEN EMT HAS A ROLE -- IS ALSO
REGULATED BY T-CELL BAY TALL,
INHIBITS LYMPHEDEMA.
SO WE CHECKED WHAT'S HAPPENING
HERE.
AS YOU CAN SEE, THE TGF BETA IS
CLEARLY EXPRESSED IN THE
SUBDERMAL REGIONS WHERE WE
HAVE -- CELLS AND THE PSMAD3 ARE
DOWNSTREAM -- THE BLOCKING --
KERATIN 14 EXPRESSION THICKENING
OF EPIDERMIS AND ALSO EXPRESSION
OF EMT MARKERS BY THESE VIMENTIN
POSITIVE LAYER.
SO EPIDERMIS UNDERGO EMT AND
CONTRIBUTE TO SOME OF THE
FIBROSIS AS OUR DATA SHOWS.
THE CONCLUSIONS, HYPERKERATOSIS
IS A PROMINENT FEATURE CH OF
LYMPHEDEMA IN BOTH HUMAN AND
MOUSE, KERATINOCYTES ARE THE
MAJOR SOURCE OF TH2 INDUCING
CYTOKINES IN LYMPHEDEMA.
TERIFLUNOMIDE PREVENTS
LYMPHEDEMA IN KERATINOCYTE
DEPENDENT WAY.
FURTHER QUESTIONS AND
OPPORTUNITIES, WHAT -- THERE ARE
SEVERAL BUT ONE IMPORTANT THING
IS, SEEMS LIKE LYMPHEDEMA FLUID
IS VERY IMPORTANT HERE.
THE PROTEOMIC -- WHAT IS
ACTUALLY MAKING THESE CHANGES IN
THE LEC FIBROBLASTS ARE THESE
EPITHELIAL CELLS. I WANT TO
THANK HYEUNG JU PARK, OUR
RESEARCH ASSISTANT IN THE LAB
WHO DID ALL THIS WORK FOR THE
PAST THREE YEARS, AND OF COURSE
DR. BABAK MEHRARA FOR ALL HIS
HELP AND TAKING CARE OF THE LAB,
AND THEN OUR CLINICAL ATTENDING
PHYSICIANS AND PREVIOUS LAB
MEMBERS.
AND OUR FUNDING SOURCE.
THANK YOU VERY MUCH.
I WOULD LIKE TO TAKE SOME
QUESTIONS LATER.
>> GREAT, THANK YOU, RAGHU.
IF YOU CAN STOP SHARING.
THAT WOULD BE GREAT.
WE'LL AGAIN TAKE QUESTIONS AT
THE END.
SO NEXT SPEAKER, I HAVE REALLY
NOTHING NICE TO SAY ABOUT IN WAY
OF INTRODUCTION.
SO I WILL JUST GET INTO IT
BECAUSE IT'S ME, AND I AM NOT
ABLE TO SHARE MY SCREEN FOR A
MINUTE.
DID YOU STOP SHARING, RAGHU?
>> YES.
>> ALL RIGHT, PERFECT.
THERE WE GO.
SO HOPEFULLY MY SLIDES ARE
COMING UP, AND AS I DO THAT, I
WOULD LIKE TO THANK THE
ORGANIZERS FOR -- ZORINA AND
SELEN AND ILSA AND BABAK AND
ANDREA FOR ALL THEIR EFFORTS IN
PUTTING THIS TOGETHER, AND FOR
THE INVITATION TO PARTICIPATE IN
THIS YEAR'S YET TO BE CHARTED.
IT BEEN A GREAT MEETING, REALLY
ENJOYED BEING ABLE TO
PARTICIPATE.
SO I WAS ASKED TO TALK ABOUT OUR
WORK ON THE ROLE THAT BACTERIAL
INFECTIONS PLAY IN AFFECTING
LYMPHATIC FUNCTION.
AND SO I'LL JUST HOP INTO THAT.
FIRST I HAVE NO CONFLICTS TO
DECLARE.
AND SO MY GROUP HAS LONG BEEN
INTERESTED IN THE COLLECTING
LYMPHATIC VASCULATURE AND THE
ROLE -- THE SPECIALIZED FEATURES
OF THOSE VESSELS PLAY IN DRIVING
LYMPHATIC FLOW, INCLUDING THOSE
INTRALUMINAL VALVES WE'VE HEARD
ABOUT EARLIER SWRELS AS WELE
LYMPH MUSCLE CELLS.
IN ORDER DO THAT IN MY LAB, WE
DO A LOT OF INTRAVITAL
MICROSCOPY WHERE WE'LL TAKE
ANIMALS AND PUT THEM DIRECTLY
UNDER THE MICROSCOPE, AND THIS
ALLOWS US TO FOLLOW ANY DISEASE
PROCESS LONGITUDINALLY OVER
TIME, AS WELL AS SEE HOW ANY
POTENTIAL EXPERIMENTAL
THERAPEUTIC INTERVENTION MIGHT
AFFECT THAT DISEASE PROCESS.
WE CAN ALSO LOOK ON SHORTER TIME
FRAMES AND LOOK AT MORE DYNAMIC
THINGS SUCH AS LYMPHATIC
PUMPING.
AND SO THIS WAS A TECHNIQUE
DEVELOPED IN MY LAB BY SHAN
LIAO, SHE NOW HAS HER OWN LAB AT
THE UNIVERSITY OF CALGARY DOING
LOTS OF INTERESTING WORK SO I
ENCOURAGE YOU TO CHECK OUT WHAT
SHE'S DOING AS WELL.
BUT SHAN DEVELOPED THIS.
THIS IS LEADING TO THE POPLITEAL
LYMPH NODE IN THE MOUSE BUT
BECAUSE SHE WAS DOING THIS IN
THE MOUSE NOW, IT OPENED UP ALL
THE MOLECULAR AND GENETIC MODELS
AVAILABLE IN MOUSE SYSTEMS TO BE
ABLE TO START TO THINK ABOUT AND
STUP DI HOW THIS MIGHT BE
REGULATED AT A MOLECULAR LEVEL.
IN SOME OF OUR WORK, WE'RE
REALLY INTERESTED IN SORT OF NOT
THINKING OF COLLECTING LYMPHATIC
VESSELS AS TUBES BECAUSE THEY
HAVE THESE VALVES WITH A TRACK
TILE UNIT AND THERE WILL BE
ANOTHER OFF THE SCREEN BUT
REALLY IT'S A LITTLE PUP .
SO THESE COLLECTING LYMPHATIC
VESSELS ARE REALLY A WHOLE BUNCH
OF THESE PUMPS ALL PUT IN
SERIES.
SO WE LIKE TO THINK ABOUT HOW
ALL THAT PUMPING OF THESE
INDIVIDUAL PUMPS HAS TO BE
COORDINATED IN ORDER TO GET
EFFICIENT FLOW.
I DON'T HAVE TIME TO TALK ABOUT
THAT TODAY, BUT THE WORK I WILL
TALK ABOUT IS SOME OF THE
DISEASE MODELS THAT WE'RE
INTERESTED IN, AND THE ONE I'LL
TALK ABOUT IS BACTERIAL
INFECTIONS.
SO THESE SKIN AND SOFT TISSUE
INFECTIONS ARE VERY COMMON IN
PATIENTS WITH LYMPHEDEMA.
SO LYMPHEDEMA, WE KNOW HAS THIS
IMPAIRMENT OF FLUID RETURN, BUT
THAT FLUID IS USUALLY ALSO
ENRICHED WITH ANTIGEN AND
ANTIGEN-PRESENTING CELLS, WHICH
GO TO LYMPH NODES.
AND THOSE ARE THEN DESIGNED TO
HELP INSTITUTE ROBUST IMMUNE
RESPONSES.
SO YOU HAVE BOTH FLUID STASIS
BUT ALSO -- THESE PATIENTS ARE
VERY, VERY PRONE TO GETTING
THESE SOFT TISSUE INFECTIONS.
THEY'RE VERY DIFFICULT TO TREAT,
THEY OFTEN END UP BEING
HOSPITALIZED TO GET IV
ANTIBIOTICS FOR TREATMENT, AND
THEY ALSO -- SOME PATIENTS
DEVELOP PATTERNS OF GETTING
THESE RECURRENT INFECTIONS SO
THEY BECOME BASICALLY FREQUENT
FLYERS GETTING THESE REPEATED
INFECTIONS.
SO IT'S WELL ESTABLISHED THAT
LYMPHEDEMA PATIENTS GET THESE
SKIN AND SOFT TISSUE INFECTIONS.
BUT THEN THERE'S OTHER GROUPS OF
PATIENTS THAT HAVE NO KNOWN
LYMPHATIC DYSFUNCTION BUT ALSO
GET THESE SSTIs.
SOME OF THOSE PATIENTS GO ON TO
START DEVELOPING THIS PATTERN OF
GETTING THESE REPEATED
INFECTIONS.
LOOKING LIKE LYMPHEDEMA
PATIENTS.
AND THERE'S ALSO DOCUMENTATION
IN THE LITERATURE THAT SOME
PATIENTS, AFTER AN INFECTION,
CAN DEVELOP LYMPHATIC
DYSFUNCTION.
THIS IS WORK FROM PETER
MORTIMER.
THERE'S ALSO -- PATIENTS THAT
HAVE REPEATED INFECTIONS CAN GO
ON TO DEVELOP LORNG TERM LONG TM
LYMPHEDEMA.
A YOUNG GIRL WAS OUT ON A
PLAYGROUND, GOT A CUT ON HER
LOWER LEG, IT GOT INNECTED D
AND EVER SINCE SHE'S HAD
LYMPHEDEMA IN THAT LOWER LIMB.
SO INFECTION SEEMS TO ACTUALLY
BE A SOURCE AND CAUSE
LYMPHEDEMA, WHICH THEN, OF
COURSE, IF YOU COMPLETE THAT
CIRCLE, MAKES THESE PATIENTS
MORE PRONE TO GETTING REPEATED
INFECTIONS.
SO REALLY THE QUESTION WE WANTED
TO ASK IS, HOW ARE THESE
BACTERIAL INFECTIONS AFFECT
BEING THE FUNCTION OF OUR
LYMPHATIC SYSTEM?
SO THAT WAS A PROJECT TAKEN ON
BY DENNIS JONES WHEN HE WAS A
POSTDOCTORAL FELLOW IN OUR
GROUP.
DENNIS NOW HAS HIS OWN LAB THAT
HE'S ESTABLISHED AT BOSTON
UNIVERSITY AND HE'S ALSO DOING
VERY INTERESTING WORK SO I
ENCOURAGE YOU TO CHECK OUT WHAT
HE'S DOING AS WELL.
SO WHAT DENNIS DID IS HE TOOK
ONE OF THE MORE COMMON BACTERIAL
STRAINS THAT ARE CAUSING THESE
SSTIs, AT LEAST IN THE U.S.,
WHICH IS STAPHYLOCOCCAL AUREUS,
AND SPECIFICALLY HE FOCUSED ON
METHICILLIN RESISTANT STRAIN, SO
MRSA.
SO DENNIS USED THAT MODEL THAT
SHAN HAD AND INFECTED IT WITH
MRSA, SO YOU CAN SEE OUR
UNINFECTED CONTROL ANIMAL HAVING
NICE STRONG CONTRACTIONS AND
WHEN DENNIS INFECTED WITH THE
MRSA, HE LOST THOSE STRONG
CONTRACTIONS.
SO THIS IS A NICE MODEL TO BE
ABLE TO WATCH THE WALL MOTION,
BUT IT'S HARD TO REALLY ASSESS
OUT WHAT'S HAPPENING WITH LYMPH
FLOW.
SO IN COLLABORATION WITH AN
EXPERT IN THIS HE DEVELOPED A
TECHNIQUE THAT ALLOWS US TO
MEASURE LYMPH FLOW, WHEN WE
INFECT WITH MRSA, WE LOSE THAT
PULSATILITY AND THE VELOCITY OF
THE FLOW IS BASICALLY SITTING AT
ZERO.
SO MRSA INFORECAST, WE E
ABILITY OF THE VESSELS TO
CONTRACT AND WE LOSE LYMPH FLOW.
SO WHAT'S HAPPENING?
ONE OF THE CRITICAL OBSERVATIONS
DENNIS MADE, AND JUST FOR
REFERENCE, WE MEASURE THE SORT
OF STRENGTH OF CONTRACTION USING
EJECTION FRACTION WHICH IS JUST
A THEORETICAL VOLUME THAT WOULD
GET SQUEEZED OUT WITH A SINGLE
CONTRACTION, WHAT DENNIS
OBSERVED WAS THAT THIS
IMPAIRMENT IN PUMPING WAS
BASICALLY PERMANENT.
EVEN LONG AFTER THE BACTERIA HAD
BEEN CLEARED.
THE MICE CLEAR THE BACTERIA
NATURALLY BY ABOUT DAY 30, SO
THIS IS JUST LOOKING WITH
FORMATION ASSAYS, TRYING TO FIND
THE BUGS AT DAY 30, WE CAN'T SEE
THEM, WHERE AT DAY 4 IF WE TRIED
TO DO PCR FOR GENETIC MATERIAL
FROM THE BACTERIA AT DAY 30, WE
COULDN'T FIND IT.
SO THE BUGS ARE CLEARED AND WE
SEE THIS PERMANENT IMPAIRMENT.
AND THIS WAS DIFFERENT FROM WORK
SHAN HAD DONE WHEN SHE WAS IN MY
GROUP WHEN SHE WAS STUDYING
STERILE INFLAMMATION USING --
AND SKIN PAINTING.
SO WHEN SHE CREATED STERILE
INFLAMMATION, SHE HAD BONE
MARROW DERIVED CELLS THAT WERE
PRODUCING NITRIC OXIDE THROUGH
INOS AND THEY BASICALLY CAUSED
THE PUMPING TO STOP AND VESSELS
TO DILATE.
AS THE INFLAMMATION RESOLVED,
SHAN FOUND THAT EJECTION
FRACTION AND STRENGTH OF THE
PUMPING WOULD COME BACK.
SO DENNIS SAID MAYBE THESE
BACTERIAL INFECTIONS ARE CAUSING
A VERY PROLONGED INFLAMMATORY
RESPONSE SO WE DID PROTEOMICS TO
SEE WHAT ALL THE INFLAMMATORY
CYTOKINES WERE DOING.
SO AT DAY 4, WE CAN SEE NOT
SURPRISINGLY A LOT OF
INFLAMMATION IN THE TISSUE BUT
BY DAY 60, THAT'S ALL PRETTY
MUCH RESOLVED.
BUT YET WE STILL SEE THIS NEAR
PERMANENT IMPAIRMENT IN
CONTRACTION.
SO WHAT'S HAPPENING?
SO DENNIS THOUGHT, WELL, OKAY,
WE KNOW LYMPHATIC MUSCLE IS
REALLY CRITICAL FOR THIS
PUMPING, LET'S SEE WHAT'S
HAPPENING WITH LYMPHATIC MUSCLE
CELL.
AND THIS WAS REALLY SURPRISING
TO US, BECAUSE THIS IS JUST TWO
WAYS LOOKING AT LYMPHATIC
MUSCLE.
CAN YOU SEE AFTER THE BACTERIAL
INFECTIONS, WE'VE LOST COVERAGE
OF OUR LYMPHATIC VESSEL.
THE MORPHOLOGY OF THE LYMPHATIC
MUSCLE CELLS LOOK DIFFERENT, AND
THEIR ORGANIZATION IS VERY
ABERRANT.
THIS IS TRUE AT 4 DAYS, 30 DAYS
AND EVEN OUT 260 DAYS AFTER
THESE MRSA INFECTIONS.
DENNIS ACTUALLY MEASURED FLOW
OUT AT 260 DAYS AND ALSO SHOWED
IT WAS STILL IMPAIRED.
SO THE MRSA INFECTION IS DOING
SOMETHING TO OUR LYMPHATIC MULLS
MUSSEL CELLS.
MUSCLE CELLS.
HE TOOK THEM, GREW THEM IN
CULTURE, DID A CELL VIABILITY
ASSAY AND BASICALLY SHOWED THE
MRSA MEDIUM WAS KILLING
LYMPHATIC MUSCLE CELLS.
SO FIRST WE WANT TO KNOW WHAT'S
IN THE MEDIA, SO WE TOOK A
PROTEOMIC APPROACH, WE PROBABLY
SHOULD HAVE FIGURED THIS OUT
BEFORE WE DID THIS BUT NOT
SURPRISINGLY, YOU FIND A LOT OF
BACTERIAL TOXINS IN THAT
CONDITIONED MEDIA.
FORTUNATELY FOR US, MANY OF
THOSE TOXINS WERE CONTROLLED BY
A SINGLE GENETIC ELEMENT IN THE
MRSA GENOME CALLED THE ACCESSORY
GENE REGULATOR, THE AGR.
THROUGH A VERY GENEROUS
COLLABORATOR WHO'S AT THE NIH
AND NIAID, MICHAEL OTTO, HE HAD
MADE MRSAs MUTANT FOR THE AGR,
SO HE GENEROUSLY PROVIDED THEM
TO US, SO DENNIS THEN TOOK
CONDITIONED MEDIA OFF AGR
MUTANTS, PUT THEM ON MUSCLE CELL
CULTURES AND SHOWED THE CELL
VIABILITY WAS MAINTAINED.
SO HOW ARE THE CELLS -- HOW ARE
THESE TOXINS KILLING CELLS?
WELL, A LOT OF THEM ARE -- THEY
CAUSE CELL LYSIS, SO WITH WILD
TYPE MRSA CONDITIONED MEDIA, WE
SEE A LOT OF CELL LYSIS WHICH
DISAPPEARS WITH THE AGR
CONDITIONED MEDIA.
THAT THEN TRANSLATED INTO IN
VIVO EXPERIMENTS WHERE IF WE
INFECTED WITH AGR MUTANT
BACTERIA, WE DIDN'T LOSE THAT
LYMPHATIC MUSCLE CELL COVERAGE
COMPARED TO OUR WILD TYPE MRSA.
AND ALSO THEN LOOKING IN VIVO,
PUMPING WAS MAINTAINED WITH AGR
MUTANT INFECTIONS.
SO IT SEEMS LIKE SOME THINGS
CONTROLLED BY THE AGR ARE
CAUSING LYMPHATIC MUSCLE CELL
DEATH AND IMPAIRING THE
LYMPHATIC PUMPING.
CAN WE ISOLATE ANY INDIVIDUAL
TOXIN THAT'S RESPONSIBLE FOR
THIS?
SO WE WENT BACK INTO OUR
LYMPHATIC MUSCLE CELL CULTURES
AND TOO MANY SOME OF THESE
TOXINS WE KNOW ARE IN THERE AND
JUST TOOK -- MEDIA AND STARTED
ADDING IN TOX IBS UP TOXI.
CAN YOU CAN SEE A LITTLE BIT OL
LYSIS IN THE RED AND BLACK, AND
THIS VERY POTENT AT CAUSING CELL
LYSIS.
HOWEVER WHEN WE DID THE REVERSE
EXPERIMENT WHERE WE TOOK THE
CONDITIONED MEDIA FROM BUGS THAT
JUST HAD A SINGLE TOXIN KNOCKED
OUT, IN THIS CASE, THE ALPHA
TOXIN AND THE DELTA TOXIN AND
EVEN THAT POTENT -- ALPHA, WE
DON'T SEE THE COMPLETE
RESUMPTION OF CELL VIABILITY
WITH IT JUST KNOCKING OUT
INDIVIDUAL TOXINS.
SO THIS WAS TELLING US THAT IT'S
NOT AN INDIVIDUAL TOXIN BUT
LIKELY THE COLLECTIVE EFFECT OF
ALL THESE TOXINS AND ALL THESE
PORE FRIN FORMING TOXINS PLAY
AGO ROLE IN LYMPHATIC MUSCLE
CELL.
IN VIVO TAKE THE OTHER QUET
FREQUENTLY IS, IS THIS REALLY
JUST A LYMPHATIC MUSCLE
CELL-SPECIFIC EFFECT?
AND SO THE APPROACH WE TOOK WAS
TO THEN CULTURE IN LYMPHATIC
ENDOTHELIAL CELLS.
THESE ARE SMOOTH MUSCLE CELLS
FROM BLOOD VESSELS IN THE HOUSE
AND HUMAN.
WE ALSO DID THIS WITH BLOOD
ENDOTHELIAL CELLS, AND WHEN WE
GIVE THE WILD TYPE CONDITIONED
MEDIA, MRSA CONDITIONED MEDIA,
WE DID SEE THAT SAME CELL DEATH
NOT PRESENT WITH THE AGR.
SO IT'S NOT SPECIFIC TO
LYMPHATIC MUSCLE CELLS.
I'LL SAY IF WE LOOK EARLY IN
INFECTION, ONE DAY, TWO DAYS
AFTER A MRSA INFORECAST, WHAT WE
OBSERVE IS HEMORRHAGE,
SUGGESTING THAT THE BLOOD
ENDOTHELIAL CELL LAYER HAS BEEN
BREACHED.
WE SEE LOSS OF VASCULAR SMOOTH
MUSCLE CELLS.
AND WE SEE -- IF WE DO
LYMPHANGIOGRAPHY, IF WE FILL
THOSE VESSELS WITH THE
LYMPHANGIOGRAPHY DYE, WE'LL SEE
IT LEAKING OUT SUGGESTING
LYMPHATIC ENDOTHELIAL CELLS HAVE
ALSO BEEN DAMAGED.
HOWEVER, IF WE LOOK AT DAY 30,
WE STOP TO SEE THAT LYMPHATIC
LEAK, WE SEE SMOOTH MUSCLE
COVERAGE BACK INTACT ON THE
BLOOD VESSELS AND WE DON'T SEE
HEMORRHAGE.
SO ALL THOSE CELL TYPES ARE ABLE
TO REPAIR THEMSELVES AND REPAIR
THE VESSELS, BUT THE LYMPHATIC
MUSCLE CELLS DON'T SEEM TO BE
ABLE TO HAVE THAT REGENERATIVE
CAPACITY TO REINVEST THOSE
COLLECTING LYMPHATIC VESSELS.
THE OTHER QUESTION WE GET IS IS
THIS ONLY MRSA THAT CAUSES THIS.
SO WE TRIED WITH ANOTHER BUG, AT
LEAST IN THE U.S., THAT CAUSES A
LOT OF CELLULITIS AND SSTIs,
WHICH IS STREP PYOGENES, AND
SIMILARLY WITH EITHER LOW OR
HIGH TITER INFECTIONS W WE SEE-
PARALYSIS OCCURS AND SIMILARLY
AT DAY 30 WE LOSE THAT LYMPHATIC
CONTRACTION PERMANENTLY.
WE SEE LOSS OF LYMPHATIC
COVERAGE.
SO REALLY WHERE I SEE SORT OF
QUESTIONS AND THINGS, THE GAPS
AND OPPORTUNITIES TO EXPLORE IN
THIS SPACE, IS FIRST MAIN
DRIVING QUESTION FOR US IS, WHY
LYMPHATIC MUSCLE CELLS DON'T
SEEM TO REGENERATE TO REINVEST
THESE LYMPHATIC VESSELS AFTER
INFECTION, AND THE COROLLARY TO
THAT QUESTION IS, OF COURSE, IS
IT POSSIBLE TO INDUCE LYMPHATIC
MUSCLE CELERY GENERATION TO
CAUSE THE COVERAGE AND REPAIR
THESE LYMPHATIC VESSELS TO TRY
TO RESTORE -- TO PREVENT THESE
CYCLES OF RECURRENT INFECTIONS.
TO DO THAT, I'VE BEEN TOLD BY A
VERY SMART SCIENTIST THAT TO
UNDERSTAND DISEASE, OFTEN WE
NEED TO UNDERSTAND DEVELOPMENT.
AND WE DON'T REALLY UNDERSTAND
WHERE LYMPHATIC MUSCLE CELLS
COME FROM IN DEVELOPMENT.
AND IF WE DID, WE MIGHT BE ABLE
TO THEN USE THAT INFORMATION TO
FIGURE OUT HOW TO CAUSE
LYMPHATIC MUSCLE CELERY GROWTH H
AND REGENERATION.
SO THIS IS A HUGE KNOWLEDGE GAP
IN OUR FIELD AND THIS COULD
REALLY HELP DEVELOPING BOTH
THERAPEUTICS AND BASIC
UNDERSTANDING OF OUR LYMPHATIC
SYSTEM.
SORT OF IN A DIFFERENT REALM,
I'VE BEEN YOU BE TALKING ABOUT
THESE BACTERIAL INFECTIONS BUT
WORLDWIDE THE MOST COMMON CAUSE
OF DEERM IS AN INFECTION WITH
THE PARASITE, THE FILARIAL
PAIROCYTES.
THEY ALSO HAVE WOLBACHIA,
WHETHER THAT ITSELF COULD CAUSE
LOSS OF LYMPHATIC MUSCLE CELL
COVERAGE OR THE PARASITES
THEMSELVES CAN.
BECAUSE THOSE PATIENTS CAN CLEAR
THE PARASITES WITH TREATMENT,
BUT YET THEY ALWAYS HAVE THAT
PERMANENT LYMPHEDEMA AND
PERMANENT LYMPHATIC IMPAIRMENT.
WITH THAT, I WANT TO THANK
PEOPLE THAT DID THE WORK.
THIS IS MY CURRENT GROUP, REALLY
THE WORK I SHOWED TODAY WAS
SHOWN BY DENNIS JONES WHO HAS
HIS OWN LAB AT BOSTON UNIVERSITY
AND FOUNDATIONAL WORK FROM SHAN
LIAO AT UNIVERSITY OF CALGARY.
FUNDING SOURCES FROM LE&RN AND
THE LYMPHEDEMA FOUNDATION, OF
COURSE NIH, THE MASSACHUSETTS
GENERAL HOSPITAL AND THE RULLO
FAMILY FOR SUPPORTING MY LAB.
SO WITH THAT, I THANK YOU AND
I'LL STOP SHARING.
AND NOW WE'RE MOVING INTO THE
QUESTION AND ANSWER PERIOD FROM
ALL THE SPEAKERS STARTING FROM
STAN ROCKSON, SO I ENCOURAGE YOU
TO KEEP FILLING IN THE Q & A,
AND I SEE SELEN HAS HER HAND
RAISED, SO I'M GOING TO ASK HER
TO LEAD THE FIRST QUESTION.
>> THANK YOU, TIM.
THIS WAS ANOTHER GREAT SESSION.
THANK YOU SO MUCH TO EVERYONE.
AND I WANT TO ASK TO ALL THE
PANELISTS AND MAYBE WHEN ALL OUR
WORKSHOP SPEAKERS THAT ABOUT MY
QUESTION ABOUT THE PREVALENCE OF
LYMPHEDEMA BECAUSE CURRENT DATA
CONTRIBUTED BY MANY -- MANY IN
THIS WORKSHOP, IT IS AN
ESTIMATION OF THE PREVALENCE AND
INCIDENCE, AND IT IS VERY
COMPLICATED, AND MY QUESTION OR
MAYBE YOU CAN SAY IT'S A CALL
FOR ACTION IS THAT HOW CAN WE
DETERMINE IN THE EPIDEMIOLOGY OF
LYMPHEDEMA, I THINK IT WOULD
HELP TO MOVE THE FIELD FORWARD
AND IF YOU CAN HAVE AN ACTUAL
INCIDENCE RATE, IT WOULD MAKE A
GREAT IMPACT.
LOOKS LIKE STAN IS READY TO JUMP
IN.
>> I'LL START.
SO IT'S QUITE CLEAR THAT WE NEED
RELEVANT EPIDEMIOLOGY, WHICH HAS
NEVER BEEN PERFORMED AND WHICH
NEEDS FUNDING AND NEEDS AN
INFRASTRUCTURE TO ACCOMPLISH.
A COUPLE OF INSIGHTS I CAN
PROVIDE.
ONE OF THE ESTIMATES THAT WE'VE
TRIED TO PUT FORWARD IS TO LOOK
AT THE RELEVANT PREDISPOSING
FACTORS FOR LYMPHEDEMA, LOOK AT
THE INCIDENCE OF THOSE FACTORS
IN THE GENERAL POPULATION.
THERE ARE MANY STUDIES TO SAY
THE PERCENTAGE OF PATIENTS WITH
OVARIAN CANCER THAT DEVELOP
LYMPHEDEMA IS X, OR SKIN CANCERS
OR LYMPHOMAS OR WHATEVER THE
CASE MAY BE, AND WHEN YOU
AGGRAVATE ALL OF THOSE NUMBERS
AS WELL AS PREVALENCE RATES IN
OBESITY AND FOLLOWING INFECTION
AND SO ON, WE DO COME UP WITH A
NUMBER THAT LACKS LIKE LOS
SOMEWHERE BETWEEN 5 AND
10 MILLION PATIENTS IN THE
UNITED STATES.
THE OTHER SET OF PUBLICATIONS
THAT I'D LIKE TO POINT OUT TO
THE GENERAL AUDIENCE IS THAT THE
INTERNATIONAL LYMPHEDEMA
FRAMEWORK HAS BEEN VERY
INTERESTED IN PREVALENCE RATES
OF LYMPHEDEMA AND CHRONIC EDEMA
WORLDWIDE, AND THERE ARE
RELEVANT SUBGROUPS IN A VARIETY
OF COUNTRIES THROUGHOUT THE
WORLD.
IN THE JOURNAL LYMPHATIC
RESEARCH AND BIOLOGY, WE
PUBLISHED A COMPENDIUM OF THE
STUDIES THAT WERE SPONSORED BY
ILF, AND THE NUMBERS ARE
SURPRISINGLY HIGH.
FOR EXAMPLE, ONE STUDY WHICH I
BELIEVE WAS DONE IN THE U.K.
LOOKED AT PREVALENCE RATES OF
CHRONIC EDEMA AMONG HOSPITALIZED
PATIENTS AND IT WAS AS LIE HIGH
AS HIGH AS
OVER 30%.
SO WE KNOW THE NUMBERS ARE HIVE,
BUT IN ORDER TO SUPPORT THE
RESEARCH THAT NEEDS TO BE DONE
TO DEAL WITH THESE PATIENTS, WE
REALLY DO NEED VERY RIGID
EPIDEMIOLOGIC STUDIES TO BE ABLE
TO SUPPORT WHAT WE KNOW.
>> GREAT.
THANK YOU.
DOES ANYONE ELSE WANT TO HOP IN
ON SELL IN'S SELEN'S QUEST?
>> I WANT AN ACTION ITEM, LIKE
ALL OF YOU HAVE SAY, YES, LET'S
GO DO THIS, WE CAN ACTUALLY
DETERMINE, SO THAT THE NEXT
GENERATION OF RESEARCHERS START
WRITING THEIR GRANTS SAYING THAT
THE INCIDENCE RATE OF LYMPHEDEMA
IS SUCH AND SUCH, AND IT IS SO
MUCH GREATER THAN YOU GUYS
THINK.
SO MAYBE IT WOULD HELP.
ANYWAYS.
>> WE JUST KNOW THE EXACT
NUMBER.
>> DHRUV, IF YOU WANTED TO SAY
SOMETHING?
>> YOU AND I HAVE TALKED ABOUT
THIS AND I COMPLETELY AGREE WITH
YOUR APPROACH DR. ROCKSON IS
MENTIONING.
I THINK ONE OF THE CHALLENGES,
THOUGH, IS IF YOU CAN'T DEFINE
IT, IT'S VERY HARD TO GIVE THE
INCIDENCE OF IT, AND THERE'S A
LOT OF DIFFERENT DEFINITIONS OUT
THERE FOR LYMPHEDEMA, AND UNTIL
THAT'S STANDARDIZED, YOU'RE
GOING TO HAVE TROUBLE GETTING A
GOOD NUMBER.
>> YEAH, I AGREE WITH THAT.
YOU KNOW, THE 10% NUMBER THAT
PEOPLE TALK ABOUT, YOU KNOW, 10%
INCREASE IN LIMB VOLUME, IS
ACTUALLY A BIG NUMBER.
THAT'S MORE THAN THREE STANDARD
DEVIATIONS AWAY FROM WHAT NORMAL
VARIATIONS IN ARM VOLUME IS.
SO I THINK THAT'S EXCLUDING A
LOT OF PEOPLE WHO ACTUALLY HAVE
LYMPHEDEMA.
SO I THINK THE DEFINITION IS
VERY IMPORTANT.
AND I THINK, YOU KNOW, A VERY
BIG GAP THAT EVERYONE'S TALKED
ABOUT IS BEING ABLE TO MEASURE
LYMPHATIC FUNCTION AK RALTLY,
AND THEN WE CAN SORT OF SET A
THRESHOLD THAT'S REALISTIC AS
OPPOSED TO SOME ARTIFICIAL
NUMBER THAT PEOPLE HAVE SELECTED
OUT OF THE AIR.
>> THANKS.
SO I'M GOING TO ASK -- FIRST OF
ALL I WANT TO THANK STAN AGAIN
FOR HIS WONDERFUL TALK THIS
MORNING AND FOR GIVING IT AT
5:30 LOCAL TIME A.M., SO THANKS
FOR THAT, STAN.
THERE'S A QUESTION FROMTIVE
WINEKOPF ABOUT WHETHER YOU'VE
TREATED ANY PATIENTS THAT
DEVELOPED LYMPHEDEMA BECAUSE OF
FILARIAL INFECTIONS WITH ANY OF
YOUR CLINICAL TRIALS, AND WOULD
YOU EXPECT SIMILAR INFLAMMATORY
PATHWAYS TO BE INVOLVED IN THOSE
PATIENTS?
>> WELL, I CAN ANSWER THE
QUESTION INDIRECTLY, WHICH IS TO
SAY THAT OF COURSE WE SEE VERY
LITTLE FILARIASIS HERE IN THE
UNITED STATES AND TYPICALLY THEY
ARE IMMIGRANTS FROM THE
COUNTRIES WHERE THE INFECTIONS
ARE INDEMIC.
I HAVE TREATED SOME OF THOSE
PATIENTS, NOT WITHIN OUR
CLINICAL TRIALS BUT WHAT I CAN
SAY BY EXTENSION IS THAT IN THE
KETOPROFEN WORK THAT WENT ON FOR
ABOUT 10 YEARS, WE DID HAVE THE
OPPORTUNITY TO TREAT BOTH AN
OPEN LABEL AND ACTUALLY EVEN IN
THE PLACEBO CONTROLLED
COMPONENT.
PATIENTS WITH STAGE III
LYMPHEDEMA THAT STRONGLY
RESEMBLE THE KIND OF DISEASE AND
THE SEVERITY OF DISEASE THAT WE
TYPICALLY SEE IN FILARIASIS, AND
WE DO SEE RESPONSIVENESS.
SO IT APPEARS THAT THERE IS NOT
A LATE STAGE BEYOND WHICH ONE
CANNOT MEANINGFULLY INTERVENE,
WHICH WOULD LEAD ME TO BELIEVE
THAT FILARIASIS AND FILARIATIT
LYMPHEDEMA CAN BE A TARGET IN
THE FUTURE FOR PHARMACOTHERAPY,
BUT WE HAVE A WAYS TO GO BEFORE
WE'RE GOING TO GET TO THAT
POINT.
>> THANKS.
THIS QUESTION WAS DIRECT TODAY
DHRUV BUT I THINK ALSO IS
RELEVANT, SO WE'LL LET DHRUV
ANSWER BUT YOU MIGHT HAVE SOME
COMMENT AS WELL, WHICH IS,
DHRUV, DO YOU THINK THE AMOUNT
OF CELLULAR INJURY AND
INFLAMMATION AT THE TIME OF
TRANS SECTION CONTRIBUTES TO THE
RISK OF LYMPHEDEMA?
>> THANKS, TIM.
I THINK WHEN I THINK ABOUT
CELLULAR INJURY OR INJURY
OCCURRING FROM SURGERY, I'M NOT
REALLY SURE THAT THAT'S AS
IMPORTANT AS THE OVERALL
INFLAMMATORY RESPONSE.
IT'S HARD NOT TO IMAGINE THAT
INFLAMMATION DOESN'T PLAY A
SIGNIFICANT ROLE IN THE BODY'S
ABILITY TO GENERATE LYMPHATICS.
IF YOULY SON TO DR. ROCK SOP'S
LECTURE, DR. NICOLLS' LECTURE,
YOUR LECTURE, INFLAMMATION IS
SUCH A KEY DRIVER.
AND IF YOU LOOK AT BMI, ELEVATED
BMI LEEFDZ TO LEADS TO A HF
LYMPHEDEMA, SO I THINK IT'S
ABOUT THE INDIVIDUAL'S BASELINE
INFLAMMATORY RESPONSE THAT
LIKELY PLAYS THE MOST CRITICAL
ROLE.
>> SO ONE ADDITIONAL THOUGHT IS
THAT -- AND I AGREE WITH ALL OF
THAT, THAT A COMMON PATTERN THAT
WE SEE AMONG THESE ACQUIRED
LYMPHEDEMA PATIENTS IS THAT
THERE IS THIS PERIOD OF LATENCY
AND OFTEN THERE IS EITHER A
DEFINED OR SOMETIMES AN
UNDEFINED ADDITIONAL INJURY OR
STIMULUS THAT THEN DRIVES THE
OVERDEVELOPMENT OF LYMPHEDEMA.
THE PATIENT MAY HAVE AN INSECT
BIDE BYTE OR THEY MIGHT HAVE A
MINOR TRAUMA TO THE SKIN, LET'S
SAY 9 OR 12 MONTHS OUT FROM
RADIOTHERAPY, AND THEN DEVELOP
OVERT LYMPHEDEMA.
SO I THINK WHAT WE CAN SAY BY
EXTENSION IS THAT THERE IS A
CAPACITY FOR LATENCY WHEN THERE
HAS BEEN A LYMPHATIC SURGICAL OR
RADIO THERAPEUTIC INJURY, BUT
THAT THE DEGREE OF DAMAGE IS
GOING TO DETERMINE THE EXTENT TO
WHICH THAT LATENCY CAN BE
MAINTAINED, AND CONVERSELY, THE
MORE MINOR THE TRAUMA, IT MAY BE
DEFINE THE DEGREE OF INJURY
THAT'S REQUIRED TO TRANSFORM
FROM A LATENT LYMPHATIC DAMAGE
TO ONE THAT IS OVERTLY
LYMPHEDEMA.
ONCE THE LYMPHEDEMA DEVELOPS, IT
TENDS TO BE SELF-SUSTAINING AND
ACTUALLY SELF-EXPONENTIALLY
EXPANDING.
SO IT'S REALLY THAT TRANSITION
FROM LATENCY TO ACTIVE
INFLAMMATORY RESPONSE IN THE
TISSUES.
>> THANKS.
I'M GOING TO HAND THE MIC OVER
TO BABAK TO ASK A QUESTION OF
MARK SHA
MARC SCHAVERIEN.
YOU WERE ASKING ABOUT HOW
PATIENT OUTCOMES AFTER --
>> O I REMEMBER NOW.
YES.
>> SORRY TO PUT YOU ON THE SPOT.
>> MY LYMPHATICS TO MY BRAIN
AREN'T WORKING VERY WELL.
MARC, I HAD A QUESTION.
DO YOU FIND THAT ANY OF YOUR
PATIENTS GET WORSE AFTER
SURGERY?
WE FIND THAT SOME OF OUR
PATIENTS GET BETTER BUT THERE
ARE SOME WHO DON'T GET BETTER
AND SOME WHO ACTUALLY GET A
LITTLE BIT WORSE.
AND IF SO, HAVE YOU IDENTIFIED
PATIENT POPULATIONS THAT MAY
MOST BENEFIT FROM LYMPH NODE
TRANSPLANT?
>> THANKS, BABAK.
SO I DON'T THINK WE HAVE
PATIENTS THAT HAVE GOT WORSE.
THAT PROBABLY COMES DOWN TO THE
PATIENT SELECTION.
SO IT'S REALLY IMPORTANT THAT
PATIENTS ARE COMPLIANT, AND IF
WE HAVE THEM STABLE AND
PLATEAUING BEFORE THEY GO TO
SURGERY, AND THEN THEY CONTINUE
THAT AFTER SURGERY UNTIL WE
START SEEING AN IMPROVEMENT,
THEN WE WOULDN'T EXPECT THEM TO
GET WORSE.
NOW THERE IS A POPULATION THAT
DOESN'T SEEM TO BENEFIT, AND
THAT'S WHAT I WAS ALLUDING TO IN
THE KNOWLEDGE GAPS, AND REALLY
THOUGHT PROVOKING SOME OF THESE
TALKS, THESE PATIENTS HAVING A
HIGH INFLAMMATORY STATE, THESE
PATIENTS ARE VERY HARD TO
CONTROL WITH CONSERVATIVE
THERAPY AND WITH SURGERY, AND I
DO CERTAINLY IDENTIFY THERE
SEEMS TO BE A RELATIONSHIP
WITH -- CHEMOTHERAPY, AND
PREVIOUS INFECTIONS.
SO REALLY I'M UNSURE AS TO
WHETHER THEY AT BASELINE HAVE A
HIGHER INFLAMMATORY RESPONSE OR
WHETHER IT IS SIMPLY KIND OF
ACCUMULATED INJURY FROM THE
TREATMENTS AND THEN EPISODES OF
INFECTION THAT MAYBE LEAD INTO
THIS HIGHLY INFLAMMATORY STATE.
I THINK THESE PATIENTS WILL BE
BEST MANAGED IN THE FUTURE BY --
CO-MANAGED WITH SURGERY AND WITH
ANTI-INFLAMMATORY MEDICATIONS
AND WE'RE REALLY EXCITED TO SEE
NEW THINGS POTENTIALLY BEING
CHARTED THAT MIGHT BE IN THE
PIPELINE.
>> THANK YOU.
SHELLEY, THERE'S A QUESTION
ABOUT WHETHER YOU COMPARED YOUR
IMAGING OF LIPEDEMA TO OBESE
PATIENTS, ESPECIALLY THOSE THAT
HAVE AS A FAMILY CARRY MORE
WEIGHT IN THEIR HIP AND LOWER
EXTREMITY REGIONS, AND IF SO,
WERE THERE ANY DIFFERENCES?
>> SURE.
THANKS FOR THE QUESTION.
SO I THINK IT'S A GREAT IDEA TO
KIND OF -- IF I UNDERSTAND THE
QUESTION RIGHT, GO AHEAD AND
SUBPARSE OUT LIKE THE CONTROL
GROUP WITH OBESITY, DEPENDING ON
THEIR BODY COMPOSITION.
I'M JUST SAY THE DATA WE
PRESENTED IN LIPEDEMA HAS BEEN
COMPARED TO BMI-MATCHED COHORTS.
SO SOME OF THOSE ARE OBESE, SOME
ARE NOT, BUT ALL OF THE DATA
WE'VE LOOKED AT SO FAR IS
COMPARING LIPEDEMA TO THOSE WITH
SIMILAR OBESITY BUT WITHOUT
LIPEDEMA, AND THEY'RE
DIFFERENTIATED BASED ON OTHER
CHARACTERISTICS LIKE WHETHER
THEY HAVE EASY BRUISING OR PAIN.
SO -- AND THEN THE QUESTION
LEADS WHETHER SOMEONE WITH --
WHO CARRIES THEIR WEIGHT AS AN
OBESE PATIENT IN THE LOWER
EXTREMITIES ALREADY, AND WE
MIGHT WANT TO QUESTION WHETHER
THEY HAVE LIPEDEMA AND THAT'S
ONE THOUGHT.
BUT THERE ARE OTHER CONDITIONS,
MAYBE HYPOTHYROIDISM THAT CAN
CHANGE PEOPLE'S WEIGHT
DISTRIBUTION.
SO I THINK IT'S A GREAT IDEA TO
KIND OF LACK AT THAT LOOP
SEPARATELY AND I APPRECIATE THE
SUGGESTION TO DO THAT, BUT AT
THIS TIME, WE HAVEN'T LOOKED AT
DIFFERENT CLASSIFICATIONS WITHIN
THE OBESE COHORT.
I HOPE THAT ANSWERS THE
QUESTION.
EMAIL ME IF NOT, WHO ASKED ME.
>> AND THEN YOU HAD A QUESTION
FOR DR. SCHAVERIEN AND MAYBE
DHRUV AS WELL.
>> BASICALLY HOW DYNAMIC IS THE
FIBROSIS, IS THAT THE ONE WE'RE
TALKING ABOUT?
>> THAT OR -- THAT PLUS THE
PERINODAL FAT QUESTION.
>> FOR THOSE WHO'VE BEEN DOING
SURGERIES IN PATIENTS WITH LYMPH
NOID TRANSPLANT, HOW IMPORTANT
IS THE ADIPOSE TISSUE OR FROM
THE SITE OF TRANSFER AND WHAT
MARKERS WOULD YOU WANT TO KNOW
ABOUT THAT ADIPOSE TISSUE
FUNCTION THAT MIGHT IMPROVE THE
THERAPIES THAT YOU'RE PROVIDING?
>> THANK YOU.
I CAN ANSWER THE FIRST PART, I
PROBABLY CAN'T ANSWER THE SECOND
PART OF THAT.
IT'S REALLY IMPORTANT TO BRING
THAT PERINODAL TISSUE.
TRANSPLANT IS A -- ASIDE FROM
LYMPH NODES IN THE TISSUE THAT
YOU WANT TO TRANSPLANT.
SO -- AND THAT'S PARTICULARLY
THE CASE FOR INTERABDOMINAL
TRANSFERS.
FOR THE -- I THINK IN SOME
CASES, THESE ARE IMPORTANT TO
ACTUALLY TRANSFER -- THERE ARE
INITIAL BENEFITS FROM
TRANSFERRING THE SKIN --
LYMPHATIC VESSELS AS A
COMPOSITE, AND I HAVE FOUND IF
YOU SUBSEQUENTLY REMOVE THAT
SKIN PADDLE, IT CAN HAVE A
SLIGHT DET RISM TO THE FINAL
RESULT, SO THERE'S MANY
INTERESTING THINGS GOING ON
HERE, EVEN BEYOND JUST THE LYMPH
NODE COMPONENT ITSELF, BUT
HAVING SAID THAT, THE LYMPH NODE
COMPONENT AND ITS PERINODAL
LYMPHATIC TISSUE, IN MY OPINION,
IS REALLY THE MAIN POWERHOUSE OF
THESE TRANSPLANTS.
IT IS A VERY POWERFUL TREATMENT
IN WELL SELECTED PATIENTS.
PRETTY MUCH I'M USING IT FOR
MOST STAGES OF LYMPHEDEMA NOW,
APART FROM THOSE PATIENTS VERY
EARLY WHO WERE PAST CANDIDATES
AND CAN AVOID A MORE COMPLEX
POTENTIALLY MORE BIG SURGERY,
AND THEN THOSE WERE VERY SEVERE,
LARGE EXTREMITIES THAT ARE A
FUNCTIONAL ISSUE, THOSE PATIENTS
ARE BEST TREATED FIRST BY
DEBULKING SUBSEQUENTLY, LYMPH
NODE TRANTS TRANSPLANTS ONCE
BEEN DOWN STAGED.
I CAN'T ANSWER YOUR OTHER
QUESTION.
>> ACTUALLY I'M GOING TO MOVE
THE CONVERSATION BECAUSE I SORT
OF HAVE A QUESTION FOR MARK
NICOLLS.
IT'S REALLY SORT OF INSPIRED BY
LISTENING TO ROCHELLE'S TALK,
WHICH WE'VE HEARD ABOUT ALL THE
INFORMATION THAT'S BEEN
HAPPENING WITH LYMPHEDEMA, AND
CHELLI IS SLOWING THIS ELEVATED
SALT CONTENT.
COULD SODIUM IN THE SKIN
ACTUALLY BE TRIGGERING SOME OF
THESE PATHWAYS?
MAYBE CHELLI WANTS TO JUMP IN ON
THAT AS WELL.
>> I'M GOING TO LET CHELLI JUMP
IN.
>> THANKS FOR RECOGNIZING THAT
SODIUM IS VIEWED AS INFLAMMATORY
IN JOINT DISEASES, AND I'M
THINKING OF THE SODIUM MRI
LITERATURE.
I'M LESS FAMILIAR OBVIOUSLY WITH
THE INTERSTITIAL PHYSIOLOGY BUT
MY UNDERSTANDING IS THAT SODIUM
HAS A RECEPTOR ON CERTAIN EITHER
MACROPHAGES OR IN DIFFERENT
IMMUNE CELLS, THE -- BP BINDING
PROTEIN AND IT'S A SENSOR FOR
SODIUM IN THE INTERSTITIAL
SPACE.
SO I HAVE A LOT OF QUESTIONS
THAT FOLLOW UP FROM THAT
OBSERVATION IN THAT STUDY, BUT I
THINK THERE'S POTENTIAL FOR TO
BE PART OF THE STORY.
I WOULD BE CAUTIOUS TO SAY THAT
SODIUM IS DIRECTLY A DRIVER
BECAUSE I THINK THERE'S A LOT OF
THINGS GOING ON IN THE LYMPH
FLUID, THESE NICE INVEE STROH
STUDIES, RAGHU'S STUDY AS WELL
SHOWED THAT FROM THESE MARKERS,
SODIUM IS ONE PART OF THAT BUT
MAYBE THESE OTHER MARKERS AS
WELL THAT CAN INDUCE
INFLAMMATION.
>> AND SELEN, I THINK YOU HAVE A
QUESTION FOR RAGHU?
>> YEAH, RAGHU, I WAS GOING TO
ASK, IT LOOKS LIKE YOU
DETERMINED QUITE A BIT OF
MARKERS, INFLAMMATORY MARKERS
AND OTHERS IN THESE LYMPHEDEMA
PATIENTS.
SO CAN THOSE BE USED FOR
BASICALLY LOOKING FOR THE
DIAGNOSTIC PURPOSES OR MARKING
THE STAGES?
>> I THINK IT'S MORE OF A
CLINICIAN'S QUESTION.
A CLINICIAN CAN ANSWER IT BETTER
THAN ME.
AS FAR AS I KNOW -- IB FLAM TRIN
PATIENT SO MAYBE THAT COULD BE
USED AS A DIAGNOSTIC MARKER, BUT
FROM OUR STANDPOINT BASED ON MY
DATA, BASED ON OUR DATA, THE
KERATIN UPREGULATIONS SEEMS TO
BE -- COULD BE POTENTIALLY BE
USED AS A DIAGNOSTIC MARKER, BUT
AGAIN -- CAN ACTUALLY ANSWER
THIS -- LIKE BABAK CAN ANSWER
THIS QUESTION BETTER THAN ME.
>> DO YOU WANT TO JUMP IN,
BABAK?
>> SURE.
YOU KNOW, I THINK THE PROBLEM
WITH SOME OF THE SKIN STUFF IS
WE NEED TO DO A BIOPSY AND I
THINK THAT'S INVASIVE.
I THINK MAYBE WE CAN TEAM UP
WITH RACHELLE TO LOOK UP FOR
NONINVASIVE WAYS TO ASSESS SKIN
CHANGES.
I THINK THAT MAY BE COOL AND
INTERESTING.
I DO THINK IT ONE OF THE FIRST
MANIFESTATIONS OF LYMPHEDEMA WE
SEE, THE SKIN, EVEN IN PATIENTS
WITH MILD DISEASE, IT'S
DEFINITELY DIFFERENT IF YOU LOOK
AT IT AND ALSO IF YOU ME SAWYER
SKIN FLUID CONTENT AND OTHER
THINGS THAT WE CAN DO SO
NON-INVAI CIVIL.
NONINVASIVELY.
THE METHODS WE USE NOW LIKE
BIOIMPEDANCE OR CENTIMETER
CHANGES AND THINGS LIKE THAT.
SO I HOPE THERE ARE GOOD SORT OF
NONINVASIVE WAYS TO QUANTIFY
CHANGES IN THE SKIN, AND I THINK
THAT COULD BE USED.
>> I THINK WE HAVE TIME FOR ONE
LAST QUESTION SO I WANT TO USE
MY MODERATOR AND ASK DHRUV A
QUICK QUESTION.
BECAUSE THIS IS SOMETHING I'VE
BEEN INTERESTED IN IN HOW AGING
IS AFFECTING LYMPHATIC FUNCTION
AND THERE'S A QUESTION FROM
DEANN NA.
DOES THE LYMPHATIC ANATOMY IN
THE ARM CHANGE WITH AGING.
>> IN THE OR WE IDENTIFY FEWER
LYMPHATIC CHANNELS BUT IN TERMS
OF AGING, FROM EITHER ONE, WE
REALLY DON'T HAVE THE DATA.
WE'RE JUST TRYING TO FIND
BASELINE ANATOMY AT THIS POINT,
AND I HOPE WITH THE R01 AND WHAT
WE'RE CURRENTLY DOING, WHICH IS
LOOKING AT A HEALTHY FEMALE
POPULATION, AGAIN, I HAVE A
GLIMPSE INTO SOME OF THESE.
I HEARD, MAYBE I'M WRONG, THAT
YOU HAVE SOME THOUGHTS ON AGING
AND LYMPHATICS?
>> I THINK WE'RE DOING SOME
EARLY PRELIMINARY WORK ON AGING.
IT'S INTERESTING, IF YOU LOOK AT
A LARGE COHORT OF PATIENTS WITH
LYMPHEDEMA, AGE IS VERY WEAKLEY
ASSOCIATED WITH LYMPHEDEMA, OR
AT ALL, OR MAYBE NOT.
SOMETIMES IN SOME DATABASES THAT
HAVE BEEN REPORTED, LOWER AGE
WAS ACTUALLY A HIGHER RISK
FACTOR FOR LYMPHEDEMA THAN
HIGHER AGE.
MAYBE IF YOUNGER PATIENTS CAN
MOUNT A MORE SIGNIFICANT IMMUNE
RESPONSE.
SO I'M NOT SURE THAT THE
LYMPHATIC ANATOMY CHANGES.
WE ALL KNOW THAT IT'S NOT
PARTICULARLY PLASTIC.
WE DO KNOW LYMPHATICS DON'T WORK
AS WELL IN ELDERLY MICE AND ALSO
IN PATIENTS, AND I THINK RAGHU
AND I ARE WORKING ON SOME --
ACTUALLY YOU TOO, TIM, WE'RE
WORKING ON SOME METHODS TO TRY
AND QUANTIFY THE INTRACELLULAR
EFFECTS OF RESPONSES TO VEGF C
AND HOW THAT CONTRIBUTES TO
LYMPHATIC FUNCTION.
>> I THINK IT'S A VERY
INTERESTING -- FOR THINKING OF
FUTURE DIRECTIONS OF LYMPHATIC
RESEARCH OF HOW LYMPHATIC SYSTEM
DOES EVOLVE WITH AGING.
SO WE KNOW EVERY OTHER SYSTEM
EVOLVES WITH AGING, SO IT MAKES
SENSE LYMPHATICS DO AS WELL.
WITH THAT, WE NEED TO WRAP UP.
I APOLOGIZE TO EVERYONE WHOSE
QUESTIONS I DIDN'T GET TO.
BUT THE Q & A WILL REMAIN OPEN
SO IF YOU WERE ONE OF THE
SPEAKERS AND YOU SEE QUESTIONS
DIRECTED AT YOU, PLEASE HIT THE
Q & A AND GET THOSE RESPONDED
TO, AND I WANT TO THANK ALL THE
SPEAKERS IN THIS WONDERFUL
SESSION, AND AGAIN, THANK THE
ORGANIZERS FOR GIVING ME THE
PRIVILEGE TO MODERATE IT.
I THINK WE'RE ON BREAK NOW UNTIL
11:25, IF I HAVE THAT CORRECT?
YEP, 11:25, AND SO ENJOY YOUR
BREAK AND YOU'LL BE BACK
SHORTLY.
THANK YOU ALL.
NEXT I'M DELIGHTED TO INTRODUCE
THE MEMBERS OF OUR PATIENT
PANEL.
I'M JOINED IN THIS SESSION BY
CYNTHIA HUDSON, CAM AYALA, KASI
GROSVENOR AND TAYLOR LEWIS.
THEY'RE GOING TO TELL YOU SOME
OF THEIR PATIENT EXPERIENCES, AN
I'M GOING TO LET THEM INTRODUCE
THEMSELVES.
MY CO-MODERATOR IS BILL, WILLIAM
RIPICCI, CEO OF LE&RN.
PLEASE JOIN ME IN WELCOMING OUR
PANEL.
OKAY.
>> SURE.
IF THAT'S MY OPPORTUNITY TO
WELCOME THEM, I WILL SAY, IT WAS
ONLY A FEW YEARS AGO WHEN IT
CAME TO NIH, NO PANEL, IT JUST
WASN'T ALLOWED.
CATHY BETZ REALLY HELPED US
BREAK THE MODEL BY COMING TO THE
FRONT AND NOW YOU ALL ARE --
IT'S SO CRITICAL TO HAVE YOUR
VOICE OUT THERE RATHER THAN
BEING SPOKEN TO, HAVE THE
OPPORTUNITY TO SPEAK TO THE
PEOPLE THAT ARE ACTUALLY
ATTENDING THIS CONFERENCE TO
GIVE THEM YOUR PERSPECTIVE, AND
TO TELL THEM WHAT YOU NEED FROM
THEM.
DR. MEHRAR WILL BE HANDLING THE
FIRST PART AND AT THE END I HOPE
TO TAKE THE LAST 8 MINUTES FOR
EACH OF YOU TO HAVE A COUPLE OF
MINUTES TO TELL THIS AUDIENCE
WHAT YOU THINK IT IS THEY NEED
TO KNOW FROM YOU.
WITH THAT, DR. MEHRARA, I'LL
TURN IT BACK TO YOU.
>> THANK YOU, BILL.
I THINK WE'LL TAKE A FEW MINUTES
JUST TO GET AI ACQUAINTED WITR
PANELISTS.
IF YOU DON'T MIND GIVING JUST A
SHORT INTRODUCTION ABOUT WHO YOU
ARE AND HOW LYMPH DISEASE HAS
IMPACTED YOU, IT WOULD BE GREAT.
WE'LL START WITH CYNTHIA HUDSON.
>> GOOD MORNING, EVERYONE.
SO I'VE HAD BREAST CANCER, I WAS
DIAGNOSED IN 1998.
I HAD A MA STET A MASTECTOT
RECONSTRUCTION ALONG WITH
CHEMOTHERAPY, RADIATION, AND
BONE MARROW TRANSPLANT.
SO I'VE GONE THROUGH A LOT AND
I'VE HAD LYMPHEDEMA FOR MANY
YEARS.
AND SO THE IMPACT THAT IT'S HAD
ON ME HAS BEEN VARIED OVER THE
YEARS.
ONE OF MY MAIN CONCERNS IS JUST
ABOUT A LACK OF EDUCATION IN THE
MEDICAL COMMUNITY AND WITH
PATIENT SUFFERING FROM
LYMPHEDEMA, TO HAVE INFORMATION
TO BE EMPOWERED TO SEEK
EFFECTIVE TREATMENT.
>> GREAT.
THANK YOU.
MEX WE'LL GO TO CAM AYAL.
A.
ALA.
>> GOOD MORNING, GOOD AFTERNOON,
WHEREVER YOU'RE VIEWING FROM.
SO MY NAME IS CAM AYALA.
I'M 33.
OH, GOODNESS, I'M ACTUALLY 34.
SO 34 YEARS OLD.
AND I WAS BORN WITH PRIMARY
LYMPHEDEMA, BUT I STARTED
PRESENTING WITH THE SWELLING
SYMPTOMS PREDOMINANTLY IN MY
RIGHT LEG WHEN I WAS ABOUT 11
YEARS OLD.
SO SIMILAR TO CYNTHIA IN THE
SENSE THAT KIND OF AROUND THE
SAME TIME PERIOD, WE'VE BEEN
MANAGING OUR LYMPHEDEMA, THOUGH
HERS IS SECONDARY TO HER CANCER
BATTLE AND MIME IS PRIMARY TO BE
BORN WITH IT, WE HAVE A LOT OF
THE SAME OR SIMILAR DAILY
STRUGGLES AND CHALLENGES FROM
MANAGING THE CONDITION TO
ACCESSIBILITY TO SOME OF THE TOP
CARE PROVIDERS, WHETHER IT'S A
LYMPHEDEMA THERAPIST OR
PHYSICIANS WHO CAN HELP TREAT
LYMPHATIC DISEASE.
SO LOOKING FORWARD TO HEARING
THE REST OF THE PANELS AND
GIVING YOU GUYS SOME MORE
INFORMATION ABOUT EACH OF OUR
JOURNEYS AND WHAT WE HAVE AS A
CALL TO ACTION TO THE PEOPLE WHO
ARE VIEWING.
>> THANK YOU.
KASI GROSVENOR?
>> MY EXPERIENCE DID START AS A
TEENAGER.
I'VE REALLY STARTED NOTICING
THINGS LIKE SEVERE BRUISING IN S
WALKING WITH BLOCKS IN MY LEGS,
JUST A LOT OF PAIN WITH TOUCHING
AND SENSITIVITY AND THINGS LIKE
THAT.
EVEN WHEN I WOULD LOSE WEIGHT, I
WOULD ONLY LOSE WEIGHT ON THE
TOP HALF OF MY BODY.
I LOST 80 POUNDS AT ONE POINT
AND IT ONLY CHANGED MY LOWER
BODY BY ONE DRESS SIZE, AND
THAT'S PRETTY DRAMATIC FOR
80 POUNDS.
SO I HAVE REALLY STRUGGLED WITH
FINDING A DOCTOR THAT ACTUALLY
KNEW WHAT LIPEDEMA WAS, AND THAT
IS THE IMPORTANCE OF THIS
RESEARCH, THE MAJORITY OF
RESEARCH OUT THERE HAS REALLY
ONLY COME UP IN THE LAST FIVE
YEARS, AND THAT HAS NOT FOLLOWED
THROUGH TO CLINICIANS IN A LOT
OF CASES.
SO I AM TREATING MY LYMPHEDEMA
RIGHT NOW WITH A NUMBER OF
CONSERVATIVE TREATMENTS AND HAVE
SEEN A LOT OF BENEFITS FROM
DOING THOSE THINGS.
IT HAS IMPROVED MY SYMPTOMS AND
I'VE ALSO STARTED WITH
LYMPHEDEMA SURGERY AT JOHNS
HOPKINS UNIVERSITY EARLIER THIS
YEAR.
THANK YOU ALL SO MUCH FOR
WELCOMING US.
>> GREAT.
THANK YOU, KASI.
NEXT WE HAVE TAYLOR LEWIS.
>> HI, EVERYONE.
THANK YOU FOR HAVING ME.
I AM 28 YEARS OLD.
I HAVE GENERALIZED LYMPHATIC
ANO,
ANOMALY, ONCE CALLED
ANGIOMATOSIS.
I WAS DIAGNOSED IN 2012 AT THE
AGE OF 17.
I HAD QUITE A BIT OF SYMPTOMS
GROWING UP.
I'D SAY THEY WERE PEAKING DURING
PUBERTY, WHICH WE'RE FINDING NOW
IS PRETTY TYPICAL WITH THE
HORMONE PATHWAYS, AND I WAS
EXPERIENCING A LOT OF BACK PAIN,
A LOT OF JUST GENERALIZED BONE
PAIN, G.I. ISSUES, AND I WAS
ALSO A COMPETITIVE TENNIS
PLAYER, SO A LOT OF THAT WAS
DISMISSED THROUGH MY DIAGNOSIS
PROCESS AS INJURIES FROM TENNIS,
SO AFTER ABOUT 10 YEARS OF
TRYING TO GET A DIAGNOSIS, I
ENDED UP AT STANFORD, AND WAS
ABLE TO GET DIAGNOSED THERE
THROUGH A FEW BIOPSIES, AND WAS
PUT ON A CLINICAL TRIAL,
SIROLYMUS AT THE TIME.
RESEARCH HAS BEEN A HUGE
COMPONENT TO MY CARE.
I'M NOW ON ALPALOCIB, THE
PIC3 INHIB, TO REALLY HOPING TO
BRING A MENTAL HEALTH AND
FERTILITY COMPONENT TO THE TALK
TODAY.
I'M LOOKING FORWARD TO SPEAKING
ON THAT AND JUST HOW LIFE HAS
KIND OF BEEN INCORPORATED IN MY
HEALTH AND IT'S SOMETHING THEAZ
THEAS EASY THAT'S
EASY TO FORGET BUT IMPORTANT FOR
US.
>> GREAT, THANK YOU SO MUCH.
I'M JUST GOING TO REALLY TRY AND
GET OUT OF THE WAY AND HAVE YOU
GUYS TALK AS MUCH AS POSSIBLE,
SO BILL AND I WILL SORT OF GO
BACK AND FORTH WITH SOME TOPICS
JUST TO PROMPT YOU, BUT I WAS, I
THINK, MOST INTERESTED IN
KNOWING HOW YOUR DIFFERENT
DISEASES HAVE IMPACTED YOUR
LIFE, YOUR MENTAL HEALTH AND
FINANCIALLY WHAT'S BEEN THE
FINANCIAL IMPLICATIONS OF IT,
AND JUST HOW DOES IT -- HOWL ISS
TO LIVE SORT OF DAY TO DAY.
I THINK THAT WILL HELP THE
SCIENTISTS AND CLINICIANS THAT
ARE HERE TO UNDERSTAND WHY WE'RE
DOING THIS.
WHY DON'T WE START IN REVERSE
WITH TAYLOR AND THEN WE'LL GO.
>> SO I DEFINITELY SAY IN THE
EARLY STAGES AS A TEENAGER, I
WOULD SAY MY QUALITY OF LIFE
BECAME VERY IMPORTANT TO ME
BEFORE UNDERSTANDING THE
IMPORTANCE OF TAKING CARE OF
MYSELF.
I THINK THAT'S VERY MUCH THE
MINDSET A LOT OF TEENAGERS HAVE,
AND PEDIATRIC ONCOLOGY, AND IT
WAS INTRODUCED TO ME, THE OPTION
OF TAKING INTERFERON, AND AS A
17-YEAR-OLD GIRL GETTING READY
TO GO TO COLLEGE, THE THOUGHT OF
LOSING MY HAIR QUITE HONESTLY
WAS DEVASTATING TO ME.
I DON'T FEEL LIKE AT THE TIME
PEOPLE QUITE UNDERSTOOD WHAT
THAT WOULD HAVE MEANT FOR MY
LIFE IN COLLEGE, FOR MY SOCIAL
RELATIONSHIPS, FOR JUST ME
COPING IN A WHOLE NEW
ENVIRONMENT IS WHAT REALLY GOT
ME INTERESTED IN SIROLYM US, THE
OPPORTUNITY TO HAVE A DRUG THAT
WOULDN'T MAKE ME LOOK LIKE A
SICK PERSON.
IF YOU SEE ME ON THE STREET, I
LOOK HEALTHY, I LOOK FINE, BUT
INTERNALLY, THERE'S A LOT GOING
ON, THERE'S REALLY BESIDES MY
BRAIN A PLACE THAT MY DISEASE
ISN'T.
SO IT WAS REALLY CHALLENGING FOR
ME TO EVEN KNOW WHERE TO REACH
OUT TO GIVEN IT'S A RARE
DISEASE, THERE REALLY WASN'T
SUPPORT GROUPS, THERE WASN'T
ANYTHING THAT I COULD REACH OUT
TO, SO I FELT REALLY ALONE.
IF WASN'T UNTIL I GOT COVID WHEN
MY DISEASE PROGRESSED WHERE
SIROLIMUS WAS NO LONGER WORKING.
I REALLY PUSHED MYSELF TO GET
MENTAL HEALTH TREATMENT, I WAS
IN PRETTY DEEP DEPRESSION,
DEALING WITH A LOT OF ANXIETY.
I'M SOMEBODY WHO CAN REALLY
KICKBACK AND KIND OF LET THINGS
GO, BUT THIS IS THE FIRST TIME I
REALLY STRUGGLED, WAS ABOUT
2020.
SO ENDED UP GETTING SOME MENTAL
HEALTH TREATMENT, MEDICATION,
TREATMENT, THERAPY, AND IT'S
REALLY CHANGED MY LIFE.
IT'S MADE ME HAVE A WHOLE NEW
PERSPECTIVE.
I STARTED A PODCAST WITH MY RARE
DISEASE SISTER, IT'S OUR WAY OF
KIND OF GIVING OUT MENTAL HEALTH
UNDERSTANDING AND TO HIGHLIGHT
THE IMPORTANCE OF IT THAT I
THINK WE ALL NEED.
>> I LOVE YOUR STORY, TRACY.
I WANT TO JUMP TO CYNTHIA.
SOME OF THE THINGS WE HEAR ALL
THE TIME FROM PEOPLE WHO CALL
OUR OFFICE, ESPECIALLY THOSE WHO
HAVE CANCER, WELL, THEY CURED
YOUR CANCER, DON'T COMPLAIN.
THAT'S THE APPROACH PEOPLE HAVE
ENDED UP TAKING BECAUSE THEY'VE
FELT SO ISOLATED.
CYNTHIA, YOU'RE A GREAT ADVOCATE
AT THIS POINT.
I'M WONDERING WHAT YOUR JOURNEY
WAS AT YOUR POINT WHEN YOU FIRST
WENT THROUGH THE CANCER
DIAGNOSIS, AND THEN ENDED UP
FINDING OUT THAT YOU HAD
LYMPHEDEMA.
>> OKAY.
SO THANKS FOR THAT QUESTION,
BILL.
SO WHEN I FIRST WAS DIAGNOSED
WITH BREAST CANCER, OF COURSE
IT'S THE SCARIEST THING EVER,
AND THEN FINDING OUT MY BREAST
CANCER WAS AT STAGE III WAS EVEN
SCARIER, ESPECIALLY BEING THE
PARENT OF TWO YOUNG BOYS.
SO IT WAS KIND OF LIKE WHAT'S
THE MOST IMPORTANT THING HERE?
FIGHTING THE DISEASE, GEARING UP
FOR THAT AND MAKING SURE THAT
YOUR CHILDREN ARE GOOD.
LYMPHEDEMA WAS JUST SOMETHING
THAT WAS ALWAYS PUT ON THE BACK
BURNER.
FOR ONE, I LIVE IN NEW YORK
CITY, AND AT THE TIME THERE WAS
ONLY ONE PROVIDER THAT TREATED
IT.
AND IT WASN'T COVERED BY
INSURANCE.
SO BEING A YOUNG PARENT, I JUST
DIDN'T HAVE THE MONEY TO COVER
WHAT I NEEDED TO GET THE
TREATMENT, SO I WAS GIVEN A
PRESCRIPTION FOR A GARMENT, I
WORE IT, DIDN'T REALIZE THAT IT
WAS HELPING BY MAINTAINING THE
SIZE OF MY ARM.
AND THOUGHT IT'S NOT HELPING, MY
ARM ISN'T GET GETTING ANY SMAR
AND I CAN'T KEEP AFFORDING TO
SPEND MONEY ON THIS SO I STOPPED
WEARING T WHICH WAS THE WORST
DECISION EVER, BUT PART OF THAT
DECISION IS BECAUSE I DIDN'T
HAVE AND WASN'T GIVEN
INFORMATION ABOUT, YOU KNOW, HOW
TO TREAT AND MAINTAIN THE
LYMPHEDEMA.
SO I THINK BEING A SINGLE PARENT
AT THE TIME, FIGHTING THE
DISEASE AT THE TIME IS OKAY,
WHAT'S MORE IMPORTANT.
THE MESSAGE THAT I GOT FROM
HEALTHCARE PROVIDERS WAS
BASICALLY THIS IS JUST SOMETHING
THAT YOU HAVE TO LIVE WITH.
RIGHT?
SO -- AND IT WAS HARD TO ACCEPT.
BRU I BUT I JUST TOOK IT IN AS
SOMETHING I HAVE TO LIVE WITH,
JUST CHUCK IT UP.
>> ONE OF THE THINGS I FOUND SO
AMAZING IS NUMBER ONE SO MANY
PEOPLE COULD HAVE THE DISEASE
AND YET SO MANY OF THEM FEEL
ISOLATED AS IF THEY'RE THE ONLY
ONE IN THE WORLD THAT HAVE THIS
DISEASE.
>> YEAH.
THAT'S ACTUALLY A REALLY GOOD
POINT, BILL.
AND I WAS GOING TO ASK YOU, I
THINK -- I'M REQUESTING TO
DIRECT THIS QUESTION TO KASI BUT
ANYONE ELSE CAN ANSWER IT TOO.
A AWILL THERE'S A LOT OF
INFORMATION OUT THERE ON SOCIAL
NETWORKS AND THE INTERNET.
I THINK THAT COULD BE A GOOD OR
BAD THING.
MAYBE IT HELPS YOU SORT OF FIND
PEOPLE WHO ARE SIMILARLY
AFFECTED BUT MAYBE IT ALSO HAS
MENTAL HEALTH EFFECTS.
HOW HAS THAT HELPED YOU AND WHAT
DO YOU THINK THE IMPLICATIONS
ARE?
>> THANK YOU SO MUCH.
THAT IS SUCH AN IMPORTANT
SYMPTOM THAT I DID NOT MENTION,
IS THE MENTAL HEALTH COMPONENT.
THERE IS A PIECE OF ANXIETY THAT
COMES ALONG WITH HAVING A
CONDITION LIKE LYMPHEDEMA THAT
MOST PEOPLE WOULD NEVER
CONSIDER.
FOR EXAMPLE, WALKING INTO A
RESTAURANT AND SEEING THE CHAIRS
AND REALIZING, THEY'RE GOING TO
BE A TORTURE DEVICE AND I'M NOT
GOING TO MAKE IT THROUGH THIS
DINNER, I'M GOING TO HAVE TO
STAND BECAUSE I CANNOT SIT IN
THAT METAL CHAIR, OR WILL IT
HOLD ME.
THESE ARE THINGS LITERALLY EVERY
CHOICE THAT A WOMAN WITH
LYMPHEDEMA HAS TO GO THROUGH ON
A CONSTANT BASIS.
AND THE IMPORTANCE OF THOSE
SOCIAL NETWORKS, I WOULD SAY
HIGHLY OUTWEIGHS THE NEGATIVE
THINGS THAT YOU WILL RUN ACROSS.
I AM PART OF A GROUP OF WOMEN
THAT MEETS ON A MONTHLY BASIS
FOR A LYMPHEDEMA ROUNDTABLE, AND
THAT HAS BEEN REALLY ONE OF THE
BIGGEST THINGS THAT HAVE
IMPROVED MY MENTAL HEALTH SINCE
MY DIAGNOSIS.
LYMPHOPRESS IS A COMPANY THAT
MAKES A PNEUMATIC COMPRESSION
PUMP, AND THEY POST THAT FOR THE
PATIENTS.
I HAVE FOUND SO MUCH SUPPORT
FROM AN EMPATHETIC COMMUNITY OF
WOMEN THERE.
ON THE DOWNSIDE, THERE ARE
PEOPLE IN THE WORLD THAT
FETISHIZE DISEASES LIKE WHAT WE
HAVE, AND WE HAVE TO DEAL WITH A
LOT OF CREEPS, AND IT IS A DAILY
PART OF THE LIFE OF A WOMAN
LIVING WITH LYMPHEDEMA.
THAT ALSO IMPACT YOUR MENTAL
HEALTH, AND SO USING THOSE
SOCIAL NETWORKS TO FIND THE
EMPATHETIC WOMEN AND LEARN FROM
THEM AND TUNE OUT THE BAD HAS
BEEN A HUGE PART OF MY MOVING
FORWARD WITH LYMPHEDEMA.
>> GREAT.
HOW ABOUT IF I JUST JUMP TO CAM
BUT TO FOLLOW UP ON WHAT YOU'RE
SAYING, KASI, ONE THING I FOUND
INTERESTING, EVEN THOUGH THERE'S
FAR GREATER AWARENESS AT THIS
POINT, WE'RE STILL AT THE
BEGINNING OF GETTING WHERE WE
NEED TO GO, I FIND THAT WE GET
MORE CALLS TO OUR OFFICE AT
LE&RN NOW TALKING ABOUT SUICIDE
OR BODILY HARM THAN EVER BEFORE.
NOT BECAUSE MORE PEOPLE ARE
THINKING THAT, I JUST THINK
PEOPLE CAN ACTUALLY SPEAK ABOUT
THIS OUT LOUD.
BUT THAT'S OUR STARTING POINT.
AND THE MENTAL HEALTH PART OF IT
IS REALLY DRAMATIC.
I WANT TO TURN TO CAM AYALA.
CAM, YOU HAVE YOUR OWN REALLY
UNIQUE STORY, AND A RATHER
DRAMATIC ONE THAT PEOPLE MOST
OFTEN DON'T GO THROUGH WHEN IT
COMES TO LYMPHEDEMA, BUT IN YOUR
CASE, IT HAS, AND I'D LOVE FOR
YOU TO TALK A BIT ABOUT THAT AS
WELL, AND THE MENTAL HEALTH
ASPECTS OF WHAT GOES ALONG WITH
THAT ALSO.
>> YEAH.
AND TO GIVE BILL KIND OF A QUICK
SHOUT OUT HERE, A COUPLE MONTHS
AGO, HE RELEASED A PIECE ON
OUR -- ON THE LE&RN WEBSITE
ABOUT THE EMOTIONAL COMPONENTS
OF LIVING WITH LYMPHATIC
DISEASES, AND THAT'S ONE THING
THAT I FIND FASCINATING IN THE
UNITED STATES HEALTHCARE SYSTEM.
IN MOST STATES, A LOT OF
INSURANCE PROVIDERS REQUIRE A
PATIENT WHO'S GOING TO UNDERGO A
BARIATRIC SURGERY, FOR EXAMPLE,
TO GO THROUGH PSYCHOLOGICAL
EVALUATION BEFORE HAVING THAT
KIND OF SURGERY.
IN MY HUMBLE OPINION, I THINK
THAT'S A BIG OPPORTUNITY FOR ANY
TYPE OF LYMPHATIC DISEASE
PATIENT, IS TO HAVE THEIR CARE
PROVIDER, WHETHER IT'S THEIR
GENERAL PRACTITIONER, THEIR
ONCOLOGIST, LYMPHEDEMA
THERAPIST, WHOEVER IS PART OF
THEIR CARE TEAM, TO LET THEM
KNOW THAT, HEY, THERE'S AN
EMOTIONAL COMPONENT WITH THIS
DISEASE STATE BECAUSE IT IS
PROGRESSIVE IN NATURE, AND
CURRENTLY THERE'S NO CURE FOR
IT.
SO WHEN YOU GET THAT NEWS, THAT
REALITY THAT YOU'RE LIVING, YOU
MAY HAVE JUST WON YOUR CANCER
BATTLE BUT NOW YOU'RE GOING TO
HAVE A LIFELONG BATTLE WITH A
LYMPHATIC DISEASE, OR IF YOU'RE
LIKE ME IN MY CASE, WHERE I'VE
HAD ACCESSIBILITY TO SOME OF THE
TOP LYMPHATIC SPECIALISTS ACROSS
THE UNITED STATES, AND EVEN WITH
THAT ACCESSIBILITY, I
UNFORTUNATELY HAD TO LOSE MY
RIGHT LEG A COUPLE OF MONTHS AGO
DUE TO AMPUTATION BECAUSE OF
RECURRENCES OF INFECTION.
SO ABSOLUTELY, IT HAS IMPACTED
ME EMOTIONALLY FROM JUST MY
OVERALL BODY IMAGE, AND JUST
LIKE WITH THE ONLINE SPACE, YOU
KNOW, LIKE ANY MEDIA, YOU HAVE
TO TAKE THE GOOD AND THE BAD
BECAUSE THERE'S GOING TO BE A
LOT OF POSITIVITY ON THERE BUT
JUST AS MUCH NEGATIVITY, SO FOR
SOMEONE WHO MAY BE NEW TO THEIR
LYMPHATIC DISEASE DIAGNOSIS, I
WOULD SAY GO INTO DIFFERENT
SUPPORT GROUPS OR SOCIAL
PLATFORMS WITH AN OPEN MIND.
YOU DON'T NECESSARILY HAVE TO BE
A CONTENT CREATOR OR
CONTRIBUTOR, BUT YOU CAN STILL
CONSUME SOME OF THAT CONTENT,
AND OBVIOUSLY IF THERE'S ANY
ANECDOTES THAT'S EXPRESSED ON
SOCIAL PLATFORMS, MAKE SURE YOU
RUN THAT THROUGH YOUR CARE TEAM
AND REALLY BE YOUR OWN ADVOCATE.
AND THERE IS A LOT OF GREAT
SUPPORT ON THERE, BUT AGAIN, YOU
HAVE TO KIND OF WEIGH THE
POSITIVES AND NEGATIVES WITH
WHAT IS GOING TO HELP YOU KIND
OF DEAL WITH THE EMOTIONAL PART
AND THEN JUST GETTING THE RIGHT
INFORMATION AND RESOURCES
AVAILABLE SO YOU CAN HAVE A
BETTER QUALITY OF LIFE.
>> THANKS, CAM.
YOU KNOW, WHENEVER I SEE A
PATIENT WHO HAS A LOT OF
DIFFERENT SYMPTOMS OR ISSUES, I
ALWAYS TRY AND ASK THEM TO SORT
OF RANK WHAT ARE THE BIGGEST
PROBLEMS TO LOWEST PROBLEMS.
AND IN A PERFECT WORLD, WHAT
WOULD YOU WANT THE NIH OR
RESEARCHERS TO DO?
AND I THINK IF YOU CAN TRY AND
SORT OF RANK THAT, IT'S LIKE
WHAT'S THE MOST IMPORTANT THING
AND THEN WORK DOWN, THAT WOULD
BE REALLY GREAT.
I THINK ANY OF YOU CAN ANSWER.
MAYBE WE'LL START WITH TAYLOR.
>> SO I THINK A LOT OF THIS IS
BASED ON WHAT I'M FINDING, I'M
PROGRESSING THROUGH LIFE, JUST A
PERSONAL PIECE OF THIS.
I'M MARRIED AND MY HUSBAND AND I
ARE TRYING TO START A FAMILY, SO
WHAT THAT HAS LOOKED LIKE IS
MAKING SURE THAT MY MEDICATION
AND MY DISEASE IS STABLE TO
WHERE I CAN DO SO, AND SO WE'VE
GONE THROUGH THAT PROCESS.
I WAS GOING TO FREEZE MY EGGS
FOR PRESERVATION TO USE.
BUT WE HAVE FOUND THAT MY JUST
FERTILITY IS FUNCTIONING LIKE A
50 TO 60-YEAR-OLD AND A LOT OF
THAT, WE BELIEVE, IS COMING DOWN
TO THE MEDICATIONS THAT I'VE
BEEN ON AND HOW LONG I'VE BEEN
ON THEM.
IT IS NOT NORMAL FOR ME AT 28 TO
HAVE THESE ISSUES, AND WE'RE
FINDING A LOT OF OTHER YOUNG
WOMEN ON THE SAME MEDICATIONS
ARE STRUGGLING WITH THE SAME
THINGS.
SO IT'S EITHER THE DISEASE OR
THE MEDICATION BUT IT'S NOT JUST
A COINCIDENCE.
SO I THINK TALKING ABOUT
FERTILITY EARLY ON IS INCREDIBLY
IMPORTANT FOR THOSE WITH
LYMPHATIC DISEASE.
GIVEN THE PROGRESSION OF MY
DISEASE, I CAN'T CARRY A CHILD
WITH MY SPINE INVOLVEMENT, AND
IT REALLY NEVER WAS TALKED ABOUT
WITH ME AT ALL.
THE ONLY TIME IT WAS WAS THE DAY
I ARRIVED ON THE ONCOLOGY UNIT
FROM THE EMERGENCY ROOM WHEN I
WAS 17 YEARS OLD.
AND IT WAS 3:00 A.M. AND THE
DOCTOR CAME IN, THERE WAS LIKE
12 DOCTORS THAT CAME IN THAT DAY
AND ONE SAID, DO YOU WANT TO
FREEZE YOUR EGGS?
WE'RE CONSIDERING PUTTING YOU ON
CHEMOTHERAPY.
AND AT 17, I HAD NO AWARENESS
ABOUT WHAT ANY OF THAT MEANT.
I WAS IN SHOCK.
I WAS ON MORPHINE, SO NOT
THINKING RATIONALLY, AS WE KNOW.
AND MY MOM WASN'T EVEN IN THE
ROOM FOR THAT DECISION, SO I
FELT LIKE THERE'S BEEN A PIECE
OF THAT THAT'S BEEN TAKEN AWAY
FROM ME.
I DO KNOW THAT THERE'S A LOT OF
OPTIONS FOR MYSELF MOVING
FORWARD, BUT WHERE I THINK
THINGS NEED TO BE IS WE'RE
TALKING TO OUR YOUNG PATIENTS
ABOUT THEIR FER TELL, STARTING
AT FERTILITY STARTING
AT THE AGE 8 OR 10.
I DON'T THINK IT'S TOO EARLY,
THERE'S EVEN SOME INTERVENTIONS
WHERE YOU CAN REMOVE AN OVARY
AND PUT IT BACK IN WHEN THE
CHILD IS READY TO BEAR.
BUT I THINK ALL IN ALL, THAT'S
AN AREA THAT IS JUST SO
OVERLOOKED, IS OUR QUALITY OF
LIFE WITH FERTILITY, AND I WOULD
REALLY LIKE THAT TO CHANGE.
>> SO MAYBE STUDYING HOW
TREATMENTS FOR LYMPHATIC
DISEASES CAN -- WHAT EFFECTS DO
THEY HAVE ON YOUR FERTILITY AND
ALSO JUST MAKING PHYSICIANS
AWARE THAT THIS IS IMPORTANT.
CYNTHIA, YOU'VE LIVED WITH THIS
TOO, RIGHT?
YOU HAD AN ISSUE WITH THIS AS
WELL.
WHAT ARE YOUR SORT OF -- WHAT'S
ON YOUR WISH LIST AND WHAT'S
YOUR THOUGHT ON FERTILITY?
>> SO I'LL GO BACK TO EDUCATION
AND TO KIND OF ECHO OFF OF WHAT
CAM AND TAYLOR JUST SAID.
I THINK JUST LETTING PHYSICIANS
KNOW WHAT SOME OF THE SYMPTOMS
ARE AND JUST MORE ABOUT
LYMPHEDEMA WOULD BE HELPFUL,
BECAUSE I DIDN'T KNOW ABOUT
FREEZING MY EGGS WHEN I WAS
DIAGNOSED, AND I WASN'T GIVEN
THAT OPTION.
SO I DID HAVE TWO CHILDREN, AND
THE MOST IMPORTANT THING FOR ME
AT THE TIME WASN'T THINKING
ABOUT HAVING MORE CHILDREN, WAS
BATTLING MY CANCER.
BUT IN A SUPPORT GROUP, I FOUND
OUT THERE WERE TWO WOMEN THAT
WERE THERE THAT WAS GETTING THE
OPPORTUNITY TO FREEZE THEIR EGGS
AND I'M THINKING, OKAY, WHY
WASN'T I GIVEN THAT INFORMATION?
SO I THINK THAT THERE'S JUST AN
INCONSISTENCY ON WHICH PROVIDERS
HAVE MORE INFORMATION THAN
OTHERS, AND I IN FACT HAD A
CONVERSATION LIKE TWO WEEKS AGO,
WHEN I SAW MY HEMATOLOGIST, WE
HAD A CONVERSATION ABOUT THIS,
JUST THE EDUCATION AS A WHOLE,
AND A LOT OF THE THINGS THAT SHE
KNOWS ABOUT MY TREATMENT IS
BECAUSE I'VE TOLD HER AND I
FILLED HER IN, AND A LOT OF THE
RESOURCES I GOT, I GOT IT ON MY
OWN.
BUT SHE AND I BOTH AGREED THAT
MORE PEOPLE INVOLVED IN THE
TREATMENT OF PATIENTS WITH
CANCER OR THAT HAVE HAD CANCER
NEED TO BE INFORMED ABOUT
LYMPHEDEMA AND SOME OF THE
SYMPTOMS AND THE TREATMENTS AND
SO FORTH.
AND ONE THING I WANT TO ADD IS,
LUCKILY THROUGH MY CONSTANT
RESEARCH AND LOOKING UP
DIFFERENT TREATMENTS ON WHAT WAS
OUT THERE IN STUDIES, I FOUND A
DOCTOR AT SLOAN KETTERING WHO
DID SURGERY FOR LYMPHEDEMA.
SO I HAD SURGERY LAST YEAR, I'VE
HAD LIPOSUCTION THERAPY, WHICH
IS GOING TO BE FOLLOWED BY A
LYMPH NODE TRANSFER, SO JUST TO
GO BACK, I'VE HAD 24 LYMPH NODES
REMOVED, 8 OF WHICH WERE
POSITIVE FOR CANCER, AND SO WHEN
I FOUND THIS DOCTOR, I GOT -- I
THINK IT WAS IN 2020, I GOT TO
SEE HIM AND I WAS EVALUATED AND
I WAS A CANDIDATE FOR SURGERY,
WHICH I HAD LAST AUGUST.
THE CHANGE IN MY LIFE, LIKE,
ABSOLUTELY CHANGED MY LIFE, AND
SO I'M THINKING, HOW LONG WAS
THIS OPTION OUT THERE?
LIKE I'VE BEEN GETTING TREATMENT
FOR SO MANY YEARS.
WHY WASN'T I CONTACTED OR
SOMETHING SAYING, HEY, YOU KNOW,
THIS IS SOMETHING NEW THAT'S OUT
THERE, YOU COULD BE A GOOD
CANDIDATE FOR IT AND WE WANT YOU
TO COME IN.
SO I THINK ACCESS OF INFORMATION
WOULD BE A MAJOR STEP.
>> SO PHYSICIAN EDUCATION,
ACCESS TO INFORMATION AND
FERTILITY.
BILL, GO AHEAD.
>> I'M JUST GOING TO JUMP TO
KASI AND THEN CAM AS WELL ON THE
SAME THING.
YOU HAVE AN OPPORTUNITY NOW,
THIS IS NIH'S CONFERENCE THAT
THEY ARE PUTTING ON.
HOW MUCH MONEY IS NIH
NECESSARILY SPENDING IN THESE
AREAS?
ARE YOU SATISFIED WITH THAT,
WOULD YOU LIKE TO SEE IT BE
MORE, WHAT DIRECTION WOULD YOU
HAVE THAT GO?
THE MEDICAL PROFESSION, WHAT IS
IT YOU FEEL THEY NEED TO KNOW
THAT YOU HAVE THIS OPPORTUNITY
NOW TO STARE AT THEM AND SAY
THIS IS WHAT YOU DON'T KNOW,
THIS IS WHAT YOU NEED TO KNOW
AND I'M HERE TO TELL YOU.
I JUST WANT TO GIVE YOU THESE
LAST FEW MINUTES WE HAVE HERE,
FIRST YOU KASI, STRAIGHTFORWARD,
SAY IT RIGHT OUT, WHAT IS IT YOU
WANT FROM THESE TWO MAJOR
GROUPS?
>> ABSOLUTELY.
BILL, THANK YOU SO MUCH.
I WANT INVESTMENT IN RESEARCH
AND LYMPHEDEMA AND I THINK THE
NUMBER ONE GAP IS PROVIDING A
CLINICAL TEST THAT ANY DOCTOR
CAN FEEL CONFIDENT TELLING A
PATIENT, YES, YOU HAVE
LYMPHEDEMA.
I THINK THAT IS THE PRIMARY
PROBLEM FOR WOMEN BECAUSE MOST
OF US ARE NOT DIAGNOSED UNTIL
MUCH LATER IN LIFE WHEN EARLY
INTERVENTION HAS SHOWN A HUGE
IMPROVEMENT IN OUR QUALITY OF
LIFE.
A LOT OF PATIENTS AREN'T EVEN
GETTING DIAGNOSED UNTIL THE
LATER STAGES AND CERTAINLY LATER
IN LIFE, AND YOU GET DIMINISHING
RETURNS WITH CONSERVATIVE
TREATMENTS AS THEY GET FURTHER
ALONG.
THAT WOULD BE MY NUMBER ONE
GOAL.
MY NUMBER TWO GOAL FOR THE NIH
WOULD BE, LET'S GO BACK TO THE
RESEARCH THAT YOU'RE ALREADY
DOING AND LOOK FOR LYMPHEDEMA,
BECAUSE IT'S IN THERE IN THEIR
STUDIES.
IT MAY NOT HAVE BEEN CALLED THAT
OR IDENTIFIED AS THAT, FOR
EXAMPLE, COMORBIDITIES LIKE
ELERS DANLOS, AND YOU HAVE A LOT
OF PEOPLE OUT THERE THAT HAVE
MASS -- DISORDERS.
RECENTLY I WENT TO THE FAT
DISORDERS RESEARCH SOCIETY
CONFERENCE AND SEVERAL OF OUR
DOCTORS SPOKE ABOUT MAST CELL
EMBROADMENT AND YOU COULD
LITERALLY SEE EVERY PATIENT IN
THE ROOM SHAKING THEIR HEAD AND
THEY HAVE NO IDEA THEY'RE LIVING
WITH A MAST CELL DISORDER.
I HAVE FOUR PAGES OF WISH LIST
ITEMS IF YOU'D LIKE TO KNOW, BUT
IN THE INTEREST OF EVERYONE
ELSE'S TIME, I'LL PASS IT OVER
TO CAM TO ANSWER.
>> BELIEVE IT OR NOT, I'VE NEVER
HAD A COURSE IN MEDICAL SCHOOL
ON LYMPHEDEMA OR LYMPHATICS.
NOT EVEN A TOPIC THAT'S COVERED.
IT'S CRAZY TO ME.
CAM.
>> I WAS GOING TO SAY, MUCH LIKE
EVERYBODY ON THE PANEL, I THINK
WE HAVE A LONG LAUNDRY LIST OF
THINGS THAT WE WOULD LOVE TO SEE
ACCOMPLISHED IN OUR LIFETIME.
SO I WOULD KIND OF ECHO THE
SEPTEMBER IMENT OF E
SENTIMENT OF PRETTY MUCH EVERY
PANELIST AS WE UNDERSTAND
THERE'S SUCH A NEED DIRE NEER
RESEARCH ON THE LYMPHATIC SYSTEM
IN GENERAL.
EVEN IF YOU DON'T HAVE A LYMPH
DISEASE, WHATEVER CONTINUUM OF
PRESENTATION YOU HAVE, THERE'S
JUST A NEED IN GENERAL, BECAUSE
WE'RE STARTING TO UNDERSTAND THE
IMPLICATIONS OF THE LYMPHATIC
SYSTEM FOR OUR IMMUNE SYSTEM,
EARLY STAGES OF DEMENTIA,
THERE'S ALL THESE CORRELATIONS
THAT ARE THERE, THAT JUST
HAVEN'T BEEN PRIORITIZED IN THE
RESEARCH.
WORKING WITH LE&RN, THAT'S ONE
BENEFIT I HAVE, HAVING MY FINGER
ON THE PULSE OF THE COMMUNITY,
THE GLOBAL COMMUNITY, BUT
ESPECIALLY HERE IN THE UNITED
STATES, IT JUST BLOWS MY MIND
THAT WE CAN SEND A MAN OR WOMAN
TO THE MOON, BUT YET WE'RE STILL
WRAPPING UP PATIENTS LIKE
MUMMIES FOR THEIR COMPLETE
DEACON JESSTIVE THERAPY.
DECONGESTIVE THERAPY.
THERE'S GOT TO BE BETTER OPTION
FROM A DRUG OR THERAPY THAT CAN
SUBSTANTIALLY IMPROVE SYMPTOMS.
I'LL CLOSE WITH THIS.
I'VE BEEN FORTUNATE TO HAVE
ACCESSIBILITY TO SOME OF THE TOP
LYMPHATIC DOCTORS IN THE UNITED
STATES AND ARGUABLY THE WORLD,
AND EVEN WITH THAT
ACCESSIBILITY, FOR THEM TO TELL
ME THAT THEY'VE NEVER SEEN
ANOTHER PATIENT THAT HAS MY TYPE
OF PRESENTATION, THAT DOESN'T
REALLY LEAVE A SETTLING FEELING
IN MY STOMACH MOVING FORWARD
EERCHG AFTER THE
EVEN AFTER THE AMPUTATION OF
WHAT'S GOING TO HAPPEN THREE
YEARS FROM NOW, FIVE YEARS FROM
NOW.
REGARDLESS OF WHAT DISEASE YOU
HAVE AS A PATIENT, YOU DON'T
LIKE KNOWING THAT YOU'RE AN
UNKNOWN.
SO THAT DEFINITELY CAN ADD SOME
STRESS TO THE MENTAL HEALTH OF
IT AND JUST TRYING TO FIND A
BETTER QUALITY OF LIFE.
BUT WE KNOW THAT THE MONEY IS
THERE, IT JUST HAS TO BE
PRIORITIZED AND NOW IT'S UP FOR
ADVOCATES LIKE ALL THE PANELISTS
HERE AND GOING BACK TO OUR
COMMUNITIES AND RALLYING THOSE
TROOPS AND TO NOT BE IGNORED ANY
LONGER.
>> KASI, YOU MADE A REALLY GOOD
POINT ABOUT A DIAGNOSTIC TEST
FOR LYMPHEDEMA.
AND I THINK ALL OF YOU, WHEN YOU
WERE SORT OF TELLING US YOUR
STORIES, YOU TOLD US THAT
BASICALLY THE DIAGNOSIS WAS
EITHER DELAYED OR DEFERRED OR
MISTAKEN.
WHAT WERE THE EARLIEST SYMPTOMS
YOU HAD, AND HOW LATE DO YOU
THINK THE DIAGNOSIS WAS?
I MEAN, DID WE TOTALLY MISS THE
BOAT FOR ALL OF YOU?
>> MY SYMPTOMS BEGAN AS A
TEENAGER, AND I WAS GASLIGHTED
IN THE MEDICAL COMMUNITY UNTIL I
WAS 40 YEARS OLD.
IT TOOK ME TAKING A BROCHURE
FROM THE LYMPHEDEMA FOUNDATION
TO MY DOCTOR AND SITTING DOWN
AND SHOWING HER THE FACTS.
I HAVE REPORTED THESE SYMPTOMS
FOR 25 YEARS, AND I HAVE BEEN
TOLD CHRONICALLY, YOU ARE AN
OBESE WOMAN, THAT'S WHAT'S WRONG
WITH YOU.
I WAS NOT DIAGNOSED UNTIL 40,
AND I SELF-DIAGNOSED AND TOOK IN
MY DOCUMENTS AND CONVINCED MY
DOCTOR TO FINALLY GIVE ME A
DIAGNOSIS.
IT SHOULD NOT BE THAT LATE.
>> I WOULD SAY THAT I WAS
DIAGNOSED PRETTY EARLY ON, SO
RIGHT AFTER I COMPLETED
RADIATION THERAPY, WHICH WAS THE
LAST -- WELL, THE LAST PHASE OF
MY TREATMENT WAS ACTUALLY TAKING
THE DRUG TAMOXIFEN BUT PRIOR TO
THAT, IT WAS RADIATION.
EVEN THOUGH I WAS DIAGNOSED
EARLY, WAS HARD TO FIND A
PROVIDER FOR TREATMENT.
AND WHEN I DID FIND IT, I WOULD
HAVE TO PAY LIKE $2,000 OUT OF
POCKET, I HAD TO PAY FOR MY
CONSULTATION, HI TO I HAD TOR
MY GARMENTS, AND EVEN NOW THAT
THAT'S CHANGED, THERE'S STILL
NOT ENOUGH MONEY PUT INTO WHAT'S
NEEDED FOR A PATIENT TO MAINTAIN
THEIR LYMPHEDEMA.
SO I THINK THAT'S SOMETHING
THAT'S IMPORTANT THAT NEEDS TO
HAPPEN BECAUSE THIS IS SOMETHING
THAT'S NOT GOING AWAY, SO WHY AM
I ONLY ALLOWED TWO GARMENTS A
YEAR WHEN I HAVE TO SWITCH UP
BETWEEN TWO GARMENTS, AND THEN
EVENTUALLY, IF I CAN'T MAINTAIN
IT OR THE GARMENTS WEAR OUT, THE
LYMPHEDEMA IS GOING TO GET
WORSE.
SO INSURANCE COMPANIES NEED TO
BE -- NEED TO PROVIDE MORE
COVERAGE FOR CARE.
>> THAT'S INSANE.
WE DON'T HAVE TWO SHIRTS A YEAR,
I CAN'T IMAGINE HAVING TWO
GARMENTS A YEAR.
THAT'S KREADZ.
TAYLOR, WHAT ABOUT YOU?
>> SO I THINK JUST SOMETHING
THAT CAME UP IN THE CHAT TOO
THAT'S INTERESTING TO ME AND I
DIDN'T BRING IT UP EARLIER IS
THAT MY DISEASE IS ONLY TREATED
BY PEDIATRICS.
IN ARE NO ADULT DOCTORS IN THE
UNITED STATES THAT TREAT WHAT I
HAVE.
AND KIND OF GOING BACK TO A
LITTLE BIT OF WHAT CYNTHIA HAD
SAID ABOUT THE BURDEN OF JUST
TRAVEL, I TRAVEL FIVE HOURS EACH
WAY TO SEE MY PHYSICIAN.
IT'S INCREDIBLY EXPENSIVE.
I GO TO A CHILDREN'S HOSPITAL
AND SO FOLLOWING UP AND FINDING
EVEN JUST ADULT SPECIALISTS THAT
WILL WORK WITH MY ONCOLOGIST IS
INCREDIBLY CHALLENGING BECAUSE
PEOPLE DON'T KNOW WHAT I HAVE,
PEOPLE DON'T KNOW HOW TO TREAT
IT, AND OFTEN IT IS A BURDEN TO
THEM TO EVEN UNDERSTAND WHERE TO
GO WITH MY CASE.
>> CAM?
>> I WOULD SAY ONE THING THAT WE
ROUTINELY FIND, I MEAN,
CERTAINLY DOCTORS ARE BRILLIANT
PEOPLE AND THEY WANT TO COME
ACROSS AS BRILLIANT PEOPLE, BUT
IF YOU'RE A BRILLIANT PERSON AND
YOU DON'T KNOW HOW TO DIAGNOSE
OR TREAT SOMETHING, YOU HAVE TWO
CHOICES.
EITHER IT'S NOT THAT IMPORTANT
OR YOU'RE NOT A VERY GOOD
DOCTOR.
AND THE CHOICE WE GENERALLY FIND
IS THEY TEND TO MAKE YOU FEEL AS
IF YOUR DISEASE REALLY DOESN'T
DESERVE THE LEVEL OF ATTENTION
THAT YOU SEEM TO THINK THAT IT
DESERVES, BECAUSE THAT PUTS THEM
IN A BETTER POSITION.
AND I'M SURE ALL OF YOU HAVE
FOUND YOURSELF AT THE DOCTOR'S
OFFICES AND FINDING OUT AND
HAVING THEM EVEN SAY, YOU KNOW A
LOT MORE ABOUT THIS DISEASE THAN
I DO, AND I'VE LEARNED SO MUCH
FROM YOU.
AND THE FRUSTRATION THERE IS,
YOU DIDN'T GO TO THEM TO TEACH
THEM ABOUT THE DISEASE, YOU WENT
TO THEM TO BE TREATED FOR THE
DISEASE.
BUT THAT IS THE CASE WITH
MEDICINE.
AND IT'S NOT JUST IN THE UNITED
STATES.
I TRAVEL AROUND THE WORLD, AND
EVERY COUNTRY THROUGHOUT EUROPE,
ET CETERA, THE SAME THING IS
GOING ON WHEN IT COMES TO THIS
DISEASE, THESE DISEASES,
LYMPHATIC DISEASES.
>> AND I WAS GOING TO SAY, I
THINK -- I DON'T KNOW THIS FOR
SURE BUT I THINK A MAIN REASON
WHY DOCTORS GAS LIGHT PATIENTS
IS BECAUSE THEY DON'T KNOW.
INSTEAD OF SAYING I DON'T KNOW
WHAT'S WRONG WITH YOU, LET ME
LOOK FOR ANOTHER COLLEAGUE WHO
MIGHT KNOW, THEY SAY OH, IT'S
YOUR OBESITY OR WHATEVER IS AND
THEY SORT OF BLOW YOU OFF
BECAUSE THEY DON'T HAVE THE TIME
TO 50 FIND THE RIGHT PERSON
TO GO FIND THE RIGHT CONNECTION
TO GET YOU WITH.
THEY DON'T HAVE TIME TO HELP.
CAM, WHAT WERE YOU GOING TO SAY?
>> THIS KIND OF PIGGY BACKS ON
WHAT YOU WERE SAYING, AND BILL
AS WELL.
SO I WATCHED A LECTURE FROM A
PRETTY RENOWNED VASCULAR SURGEON
IN THE GREATER HOUSTON AREA
WHERE I'M FROM, AND HE EVEN GOT
HIS LYMPHEDEMA CERTIFICATION AT
THE GOLDI CLINIC IN GERMANY, ONE
OF THE TOP FACILITIES IN THE
WORLD FOR STUDYING AND TRAINING
PHYSICIANS AND THERAPISTS ON
LYMPHEDEMA TREATMENTS.
AND ONE OF THE POINTS HE MADE
FROM JUST A PURE BUSINESS
PERSPECTIVE IN THE UNITED STATES
IS, AS A VASCULAR SURGEON, HE
CAN DO A VEIN ABLATION, LIKE TWO
OR THREE OF THEM IN AN HOUR OR
TWO AND CHARGE THE INSURANCE A
COUPLE GRAND A POP, WHEREAS THE
COMPENSATION FOR TREATING ONE
LYMPHEDEMA PATIENT TO DO MANUAL
LYMPHATIC MASSAGE, THE
COMPENSATION FOR THAT IS LIKE A
COUPLE HUNDRED BUCKS.
SO FROM A PURE BUSINESS
PERSPECTIVE, A LOT OF THESE
DOCTORS ARE MAKING THEIR
DECISION BASED ON THEIR BOTTOM
LINE.
HOW CAN I MAKE MORE MONEY FROM
SEEING LESS PATIENTS, RIGHT?
AND SO THAT'S A SAD REALITY TOO,
JUST FROM THE INSURANCE
COMPENSATION, THAT AS A PATIENT,
IF YOUR INSURANCE DOESN'T COVER
THE TREATMENT, IT CAN BE VERY
EXPENSIVE AND THE DOCTORS AREN'T
NECESSARILY INCENTIVIZED IN A
LOT OF CASES BECAUSE FROM A
VENOUS PERSPECTIVE, THEY CAN
MAKE A LOT MORE MONEY DOING
VARIOUS OTHER TYPES OF VENOUS
PROCEDURES THAN IF YOU HAVE THE
LYMPHATIC DISEASE FIRST.
>> I THINK THAT'S SOMETHING THAT
CAN BE MANAGED FAIRLY
EXPEDITIOUSLY.
AT SLOAN KETTERING AND OTHER
PLACES WHERE WE WORK, WE USUALLY
GET DENIED FOR ANY LYMPHATIC
PROCEDURE WE DO.
WE DO THEM AND WE JUST SORT OF
EAT IT.
BUT WE GET DENIED 9 OUT OF 10.
AND I THINK WE COULD GO A VERY
LONG WAY IF MEDICARE STARTED TO
RECOGNIZE THESE PROCEDURES AS
NON-INVESTIGATIONAL.
SO LYMPHOVENOUS BYPASS,
LIPOSUCTION, THEY'RE ALL
CONSIDERED INVESTIGATIONAL FOR
THE TREATMENT OF LYMPHEDEMA AND
LYMPHEDEMA, BUT THEY'RE NOT.
THERE'S HUNDREDS OF PAPERS OUT
THERE THAT SHOW THAT THESE
TREATMENTS ARE EFFECTIVE.
YOU HEARD A VERY NICE TALK FROM
MARC TODAY AND ALSO FROM DHRUV,
BUT THE EVIDENCE IS PRETTY
OVERWHELMING, AND AT THIS POINT,
I THINK MEDICARE REALLY NEEDS TO
SORT OF STEP IN AND REG REC.
NIEZ THESE PROCEDURES, GIVING
THEM AN RVU AND I THINK OTHER
INSURANCE COMPANIES WILL FOLLOW.
BUT I THINK THIS IS SOMETHING
THAT COULD COME OUT FAIRLY
QUICKLY.
>> ONE THING I WANTED TO SAY,
DR. MEHRARA, YOU TALKED ABOUT
SOMETIMES DOCTORS DISMISSING
PATIENT BECAUSE THEY DON'T KNOW.
I WANT TO SAY SOME OF THE
DANGERS OF THAT, I'VE HAD
SEVERAL CELLULITIS INFECTIONS
WHERE I HAD TO BE HOSPITALIZED
MULTIPLE TIMES.
A LOT OF TIMES I GO IN, I KNOW
WHAT IT IS, I TELL THEM WHAT IT
IS, AND THEN WE GO FORWARD.
BUT I THINK THE PROBLEM IN
DOCTORS DOING THAT OR NOT
KNOWING WHAT CERTAIN THINGS CAN
LEAD TO IS THAT CELLULITIS
INFECTION CAN BE DEADLY.
SO YOU KNOW, YOU HAVE TO KNOW
ABOUT WHAT PEOPLE WITH
LYMPHEDEMA ARE COMING IN WITH,
SO THAT YOU CAN BE ABLE TO, I
GUESS, DIAGNOSE OR PROJECT A
GOOD COURSE OF TREATMENT.
>> I THINK THAT'S A GREAT
POIFNLT I ALWAYS TELL MY
RESIDENTS AND FELLOWS THAT NO
ONE COMES IN TO THE EMERGENCY
ROOM BECAUSE THEY WANT TO, NO
ONE IS FAKING PAIN OR WHATEVER.
THEY HAVE A PROBLEM.
AND JUST BECAUSE YOU CAN'T SEE
IT, IT DOESN'T MEAN IT'S NOT
THERE, BECAUSE THE SYMPTOMS
OFTEN APPEAR WAY BEFORE WE CAN
DIAGNOSE IT.
SO I THINK THAT'S A REALLY GOOD
POINT.
I THINK THAT'S A GREAT POINT.
BILL?
WE HAVE TWO MINUTES.
ANY LAST MINUTE QUESTIONS?
>> I WANT TO THANK THE PANEL,
TAKE A MOMENT TO SAY THAT.
AS I SAY, UP UNTIL A FEW YEARS
AGO, THIS KIND OF THING WASN'T
HAPPENING.
I WAS AT ONE RESEARCHER
CONFERENCE AND IT WAS THE FIRST
TIME THIS WAS EVER DONE, AND
RESEARCHERS CAME UP AND SAID,
GEE, I'VE BEEN DOING RESEARCH
FOR 20 YEARS, I'VE NEVER
ACTUALLY MET A PATIENT BEFORE.
AND AS A RESULT, THERE WAS THIS
HUGE DISCONNECT ABOUT THE
IMPORTANCE, BUT ALSO THE POWER
OF YOUR STORIES IN A WAY THAT IT
ACTUALLY DRIVES RESEARCHERS AND
PEOPLE IN THE MEDICAL PROFESSION
TO CREATE CHANGE, AND HOPEFULLY
NIH AS WELL, TO PUT MORE
RESOURCES AND MONEY INTO
LYMPHATIC RESEARCH, NOW WE'RE
DEVELOPING THE NATIONAL
COMMISSION HOPEFULLY AT NIH THAT
CONGRESS HAS CALLED FOR, WE LOOK
FORWARD HOPEFULLY THAT ALL OF
YOU WILL BE PART OF IT BECAUSE
YOU'RE THE ONES WITH THE REAL
INFORMATION THAT WE NEED TO PUT
FORWARD FOR THIS.
I CAN'T THANK YOU ENOUGH FOR
YOUR BRAVERY IN COMING FORWARD.
AND SPEAKING FOR EACH ONE OF
YOUR COMMUNITIES AND ALSO
DEALING WITH THE MENTAL HEALTH
ISSUE THAT I JUST FIND IS SO
IGNORED BECAUSE WE HAVE SO MANY
OTHER ISSUES ON TOP OF IT, THAT
WE ARE TRYING TO FIGHT FOR, BUT
TAYLOR, YOU BROUGHT THIS UP AND
HAVE SPOKEN BEFORE AND I REALLY
APPRECIATE IT, AND I APPRECIATED
ALL OF YOU HAVING THE
OPPORTUNITY TO SPEAK ON THAT
ISSUE AS WELL, BECAUSE THIS IS A
PRETTY DEVASTATING ONE.
>> YEAH, AND I WANT TO THANK YOU
TOO, BECAUSE IT'S REALLY HARD
TO, YOU KNOW, GET IN FRONT OF AN
AUDIENCE AND SHARE YOUR STORY,
BUT I THINK IT'S IMPORTANT.
I THINK PEOPLE NEED TO HEAR IT,
AND I THINK THEY NEED TO HEAR IT
FROM PATIENTS WHO HAVE
EXPERIENCED IT.
SO I REALLY WANT TO THANK YOU
FOR TAKING THE TIME TO DO IT.
>> THANK YOU SO MUCH.
>> WE HAVE SOME QUESTIONS BUT I
THINK MOST OF THEM WERE ANSWERED
IN THE Q & A, SO I THINK WE'LL
TAKE A BREAK AND THANK AGAIN
EVERYONE FOR JOINING US.
>> BABAK, CAN YOU PASS TO
PATRICIA, PLEASE?
>> YES, I'M GOING TO PASS IT --
ACTUALLY WE'RE NOT TAKING A
BREAK.
DON'T TAKE A BREAK.
>> THANK YOU.
AM I GOING TO INTRODUCE NOWM OUW
OTHER NEXT SPEAKER, DR. REEMA
RAILKAR.
SCIENTIFIC PROGRAM MANAGER IN
THE NATIONAL CANCER INSTITUTE'S
SMALL BUSINESS INNOVATION
RESEARCH, SBIR, DEVELOPMENT
CENTER.
SHE WILL TALK ABOUT SBIR AND
SMALL BUSINESS TECHNOLOGY
TRANSFER, STTR, FUNDING
PROGRAMS.
REEMA?
>> CAN YOU HEAR ME?
I'M GOING TO CHANGE MY DISPLAY
SETTINGS.
I THINK THEY SHOULD BE BETTER.
>> YES.
>> FANTASTIC.
THANK YOU SO MUCH TO THE
ORGANIZERS AND MOST IMPORTANTLY
THANK YOU TO THE PATIENTS FOR
TELLING THEIR STORIES.
I WAS LISTENING AND THIS IS
REALLY IMPORTANT, I THINK IT IS
IMPORTANT NOT ONLY FOR THE
CLINICIANS AND RESEARCHERS WHO
ARE WORKING IN THIS AREA, BUT
ALSO FOR THE DIFFERENTLY
INSTITUTES OF NIH WHEN THEY ARE
THINKING ABOUT HAVING SOME
SPECIALIZED FUNDING OPPORTUNITY
ANNOUNCEMENTS TARGETED TOWARDS A
PARTICULAR DISEASE AREA.
SO I REALLY THANK ORGANIZERS AND
THE PATIENTS FOR THE TALKS
TODAY.
WHAT I'M GOING DO IS TALK A
LITTLE BIT ABOUT THE SBIR
FUNDING OPPORTUNITIES THAT ARE
NECESSARY, THE WAY YOU CAN
COMMERCIALIZE YOUR TECHNOLOGIES
FROM LAB TO MARKET FOR THE
BENEFIT OF PATIENTS, PROVIDERS
AND CAREGIVERS.
THE SBIR PROGRAM RUNS ACROSS 11
FEDERAL AGENCIES THAT INCLUDES
DEPARTMENT OF HEALTH AND HUMAN
SERVICES, AND NIH IS A PART OF
THIS AGENCY.
THE SBIR AND STTR PROGRAMS ARE
CONGRESSIONALLY MANDATED
SET-ASIDE PROGRAMS.
WHAT IT MEANS IS THAT THOSE
FEDERAL AGENCIES ARE ONLY
BUDGETED A CERTAIN AMOUNT SET
ASIDE PART OF THE BUDGET FOR
SBIR OR SMALL BUSINESS
INNOVATION RESEARCH, AND STTR,
OR SMALL BUSINESS TECHNOLOGY
TRANSFER PROGRAM.
NIH HAS $1.2 BILLION SET ASIDE
FOR THE SBIR/STTR FUNDING.
WITHIN NIH, THERE ARE 27
INSTITUTES AND CENTERS THAT ARE
DIVIDED BY EITHER DISEASE AREA
OR ORGAN OR PARTICULAR ACTIVITY.
23 OF THESE INSTITUTES UNTIL
PINK AND RED ARE THE -- ALTHOUGH
PARTS OF MY TALK ARE PRIMARILY
RELATED TO NCI OR NATIONAL CANS
SER NATIONAL
CANCER INSTITUTE, IF THERE ARE
OTHER AREAS YOU'RE INTERESTED IN
PLEASE LET ME KNOW.
WE ALL WORK COLLABORATIVELY HERE
AT NIH AND I'M HAPPY TO CONNECT
WITH THE APPROPRIATE PERSON
ACROSS THE INSTITUTES.
LET'S TALK ABOUT THE ELIGIBILITY
FOR THE SBIR/STTR PROGRAMS.
THE AWARD IS ALWAYS MADE TO A
SMALL BUSINESS CONCERN.
THE SMALL BUSINESS MUST BE
ORGANIZED FOR PROFIT IN THE
UNITED STATES WITH 500 OR FEWER
EMPLOYEES AND ASSOCIATES.
AND THIS SMALL BUSINESS
CONSULTANT MUST BE 50% OR MORE
OWNED BY U.S. INDIVIDUALS.
WHY SEEK SBIR/STTR FUNDING?
IT IS THE BIGGEST SOURCE OF SEED
FUNDING AVAILABLE TO SMALL
BUSINESSES IN THE BIOMEDICAL
FIELD.
THIS IS A GRANT AND NOT A LOAN,
WHICH MEANS THAT IT IS A
NON-DILUTIVE TYPE OF FUNDING.
IF YOU GENERATE ANY I.P. USING
THESE FUNDS, NIH DOES NOT CLAIM
THIS I.P.: SINCE APPLICATION
GOES THROUGH NIH REVIEW PROCESS,
IT PROVIDES VERIFICATION FOR
YOUR TECHNOLOGY, AND FINALLY
ANY -- HAVING THIS GRANT IN
ATTRACTING PRIVATE FUNDING SUCH
AS -- FUNDING.
SO WHAT IS THE DIFFERENCE
BETWEEN SBIR AND STTR, AND THIS
IS REALLY IMPORTANT FOR THE
ACADEMICS WHO ARE IN THIS GROUP.
THE STTR ESPECIALLY.
SO STTR PRIORS IT IS A MUST TO
HAVE A PARTNERSHIP BETWEEN THE
SMALL BUSINESSES AND A U.S.
NON-PROFIT RESEARCH INSTITUTION
SUCH AS UNIVERSITIES.
FOR SBIR, SUCH PARTNERSHIP IS
NOT NEEDED BUT IF YOU WANT TO
HAVE IT, YOU CAN HAVE IT.
ONE OF THE MOST IMPORTANT
DIFFERENCE BETWEEN SBIR AND
STTR, AND IT IS AGAIN REALLY
IMPORTANT FOR THE ACADEMICS WHO
ARE HERE, IS THAT PI'S PRIMARY
PLACE OF EMPLOYMENT.
IN CASE OF STTR, PRIMARY PLACE
OF EMPLOYMENT IS NOT STIPULATED
WHICH MEANS YOU CAN MAINTAIN
YOUR TENURED OR TENURED TRACK
POSITION AT A UNIVERSITY WHILE
HAVING AN STTR GRANT.
IN CASE OF SBIR, THOUGH, THE
P.I. MUST BE MORE THAN 50%
EMPLOYED AT THE SMALL BUSINESS
CONCERN.
THE SBIR/STTR PROGRAMS PROVIDE
THE FUNDING BASED ON MILESTONES
ACHIEVED DURING THE DIFFERENT
PHASES.
PLEASE DO NOT CONFUSE THEM WITH
THE PHASES OF CLINICAL TRIALS.
THESE ARE THE PHASES OF FUNDING.
SO YOU MAY SPHART START WIT,
PROVE OF CONCEPT, PHASE TWO IS
RESEARCH AND DEVELOPMENT.
ONLY FOR SBIR YOU CAN ALSO APPLY
FOR THE DIRECT TO PHASE TWO IF
YOU ALREADY HAVE FINISHED PROOF
OF CONCEPT STUDIES FOR YOUR
TECHNOLOGY, AND SOME INSTITUTES
OF NIH PROVIDE A FOLLOW-ON
FUNDING FOR PHASE TWO AWARDEES
CALLED PHASE 2B BRIDGE AWARD TO
BRIDGE THE GAP CALLED VALLEY OF
DEATH BETWEEN THE END OF FEDERAL
FUNDING AND THE BEGINNING OF
PRIVATE FUNDING.
WE GET A NUMBER OF QUESTIONS
REGARDING THE BUDGET GUIDELINES.
SOME OF THE OTHER INSTITUTES OF
NIH HAVE EVEN BIGGER -- HAVE
ABILITY TO FUND EVEN LARGER
PROJECTS FOR MANY TOPICS, AND A
LOT OF BUDGET FLEXIBILITIES
ACROSS NIH SO IT IS REALLY
IMPORTANT THAT YOU CONTACT THE
PROGRAM OFFICER BEFORE
SUBMITTING A PROPOSAL.
NOW LET'S TALK ABOUT DIFFERENT
FUNDING VEHICLES AT NIH.
GRANTS SUCH AS INVESTOR
INITIATED OMNIBUS SOLICITATIONS
OR TARGETED FUNDING
OPPORTUNITIES MAKE UP THE
BIGGEST CHUNK OF FUNDING.
THERE ARE THREE RECEIPT DATES
FOR THE GRANTS.
JANUARY 5TH, APRIL 5TH AND
SEPTEMBER 5TH OF EVERY YEAR.
SOME ICs SUCH AS NATIONAL
CANCER INSTITUTE IS -- AS A
MECHANISM TO FUND SCIENTIFIC AND
TECHNOLOGY PRIORITY AREAS OF
NCI.
KEEP IN MIND THESE ARE NOT THE
SERVICE CONTRACTS, THESE ARE
RESEARCH AND DEVELOPMENT
CONTRACTS.
EVERY YEAR NCI SOLICITS EIGHT TO
15 NEW CONTRACT AREAS AND I'M
GOING TO COME BACK TO ONE OF THE
CONTRACT TOPIC AREAS THAT WE
SOLICITED LAST YEAR THAT HAVE
STRONG POTENTIAL FOR COMMERCIAL
SUCCESS.
>> 2 MINUTES REMAINING.
>> HOW MANY?
>> 2 MINUTES.
>> SURE.
I'M JUST GOING TO -- SO THESE
ARE SOME OF THE FUNDING
OPPORTUNITIES.
IN THE INTEREST OF TIME, I'M
GOING TO GO A LITTLE FURTHER
AHEAD.
SO THE MAJOR DIFFERENCE BETWEEN
SBIR AND STTR GRANT AND ACADEMIC
GRANT IS A FOCUS OF SCIENCE.
IN CASE OF SBIR GRANTS, THEY'RE
FOCUSED ON CREATION OF PRODUCT
AS OPPOSED TO ACADEMIC GRANT,
WHICH IS BASED ON
HYPOTHESIS-DRIVEN SCIENCE.
THERE PRODUCT COULD BE A DRUG,
COULD BE A DIAGNOSTIC TEST,
COULD BE A RESEARCH TOOL OR
DEVICE OR EVEN A DIGITAL HEALTH
APP.
THE APPLICATIONS ARE JUST BASED
ON IF THE PROPOSED PRODUCT HAS A
COMPETITIVE ADVANTAGE OVER THE
OTHERS IN THE SAME AREA.
SO FOR EXAMPLE, DOES IT CHANGE
THE PARADIGM HOW THE DISEASE IS
TREATED OR DIAGNOSED, AND IF TH-
HAS ENOUGH EXPERIENCE.
GRANT APPLICANTS ALSO NEED TO
DESCRIBE HOW THEY WILL
COMMERCIALIZE ANY PRODUCT.
THESE ARE DIFFERENT WAYS HOW YOU
CAN COMMERCIALIZE YOUR TECH WITH
SBIR.
YOU CAN EITHER START YOUR OWN
COMPANY OR YOU CAN PARTNER WITH
AN EXISTING COMPANY OR AN
EXISTING SMALL BUSINESS TO
CONTINUE AS A P.I.
OR BY PARTNERING WITH AN
EXISTING SMALL BUSINESS.
EACH HAVE PROS AND CONS WHICH I
HAVE LISTED HERE.
SO WHY THE INTEREST IN LYMPHATIC
DISEASE, AND THE SHORT ANSWER IS
LYMPHEDEMA, ABOUT WHICH I REALLY
LEARNED A LOT IN TODAY'S MORNING
TALKS.
SO YOU KNOW, THIS AUDIENCE NEEDS
NO INTRODUCTION, THEY NOW HOW
DEBILL
DEBILITATING IT IS.
LAST YEAR WE PUBLISHED A
CONTRACT TOPIC TO DEVELOP NEW
TREATMENT MODALITIES FOR CANCER
PATIENTS SUFFERING FROM
LYMPHEDEMA.
THIS CONTRACT TOPIC IS NO LONGER
ACTIVE BUT MAY COME BACK IN THE
NEXT COUPLE OF YEARS.
IN ANY CASE, IF YOUR SMALL
BUSINESS HAS A TECHNOLOGY THAT
WILL BENEFIT THE EARLY DIAGNOSIS
OR TREATMENT OR PREVENTION OF
LYMPHEDEMA OR ANY OTHER
LYMPHATIC DISEASES FACED BY
CANCER PATIENTS, PLEASE CONTINUE
SUBMITTING AN SBIR/STTR GRANT
VIA THE OMNIBUS MECHANISM TO THE
NCI SBIR.
THESE ARE THE PROGRAM DIRECTORS
AND THEY DEAL ONLY WITH THE
SBIR/STTR GRANTS AND CONTRACTS
AND NOT WITH ANY ACADEMIC GRANTS
SUCH AS R01.
SO IF YOU'RE PLANNING TO SPLIT
SBIR/STTR GRANTS, SEND YOUR
SPECIFIC AIMS PAGE, WE HAVE THE
EMAIL GIVEN HERE.
THIS IS OUR CONTACT INFORMATION,
AND DIFFERENT SOCIAL MEDIA
INFORMATION.
AND I WILL STOP HERE AND STOP
SHARING MY SLIDES.
>> THANK YOU, REEMA.
ARE THERE ANY QUESTIONS FOR
DR. RAILKAR?
SELEN, YOU HAVE A QUESTION?
>> YES.
REEMA, I WAS GOING TO ASK ONE OF
THE MOST COMMON QUESTIONS THAT I
GET FROM OUR APPLICANTS IS THAT
THEY ARE MORE FAMILIAR WITH THE
RESEARCH GRANT AND WHAT'S THE
ROAD MAP OF A SUCCESSFUL
SBIR/STTR GRANT, IF THEY NEED A
BUSINESS PLAN?
>> SO FOR PHASE ONE, YOU DO NOT
NEED A BUSINESS PLAN.
AND IF YOU HAVE NEVER APPLIED
FOR A SBIR/STTR GRANT BEFORE, A
NUMBER OF DIFFERENT INSTITUTES
AT NIH INCLUDING NCI, NHLBI, AND
OTHERS, HAVE A PROGRAM CALLED
APPLICANT ASSISTANCE PROGRAM.
THIS IS NOT A GRANT-WRITER, BUT
THEY ACTUALLY HELP YOU, IF YOU
GET SELECTED, IT'S A COMPETITIVE
PROGRAM FREE OF COST TO THE
APPLICANT, AND IF YOU GET
SELECTED, THE NIH CONTRACTOR
HELPS YOU.
IT'S A 10-WEEK PROGRAM, TO WRITE
YOUR GRANT, SO FOR EXAMPLE, THE
WEEK ONE IS BASICALLY, YOU KNOW,
YOU HAVE TO COME UP WITH YOUR
OWN RESEARCH STRATEGY.
BUT THEY WILL GUIDE YOU HOW TO
DEVELOP THE BUDGET, HOW TO
DEVELOP THE WHOLE, YOU KNOW,
SPECIFIC AIMS PAGE AND ALL THOSE
DIFFERENT THINGS.
SO ONE OF THE WAYS IS FIRST OF
ALL COMMIT TO THE PROGRAM
DIRECTORS.
WE HAVE A LOT OF OUTREACH EVENTS
AND THIS WAS JUST 10 MINUTES BUT
WE DO A LOT OF DIFFERENT
OUTREACH EVENTS THAT GO UP TO AN
HOUR, HOUR AND A HALF WHERE WE
ACTUALLY GO IN DETAILS HOW TO
WRITE THESE GRANTS.
SO THOSE ARE A COUPLE OF WAYS
YOU CAN WRITE THE SBIR/STTR
GRANTS.
>> THANK YOU.
>> THANK YOU, REEMA.
ARE THERE ANY OTHER QUESTIONS?
WELL, SO I GUESS IT NOW TIME TO
TAKE A BREAK FOR LUNCH.
AND WE WILL BE BACK TO START
SESSION NUMBER SEVEN AT
1:30 P.M. EASTERN TIME.
THANK YOU ALL.
THANK YOU ALL FOR A WONDERFUL
MORNING.
>>IT'S 1:30.
LET'S GET STARTED WITH THE LAST
SESSION.
>> OK, GREAT.
IT'S MY PLEASURE NOW TO
INTRODUCE OUR CO-CHAIR, Dr.
ANDREA RADTKE.
SHE'S A ASSOCIATE SCIENTIST
WITHIN THE INTRAMURAL PROGRAM AT
THE NIH INSTITUTE OF ALLERGY AND
INFECTIOUS DISEASES AND SHE
SPECIALIZES IN VAST FACIAL
MAPPING OF DIVERSE TISSUE.
PLEASE JOIN ME IN WELCOMING HER.
>> THANK YOU, BABAK.
YEAH, IT'S MY PLEASURE TO
MODERATE THIS SPECIAL SESSION,
OUR LAST SESSION OF THE TWO-DAY
SYMPOSIUM FEATURING NEW
TECHNOLOGIES IN LYMPHATIC
IMAGING AND MAPPING.
THE TECHNOLOGIES DISCUSSED HERE
PROVIDE EYE MEANS TO EVALUATE
THE LYMPHATIC SYSTEM ACROSS
SCALES FROM SINGLE-CELL TO MACRO
ANATOMICAL STRUCTURES TO DATA
FROM CLINICAL COHORTS.
IT'S OUR HOPE THE NEW
TECHNOLOGIES OUTLINED HERE
ADVANCE OUR UNDERSTANDING OF THE
HUMAN LYMPHATIC SYSTEM WHILE
PROVIDING A MEANS TO IMPROVE THE
TREATMENT AND PREVENTION OF
LYMPHATIC DISEASES.
OUR FIRST SPEAKER THIS SESSION
IS MAX.
Dr. MAX ITSKIN, THE DIRECTOR
OF THE PENN CENTER FOR DISORDERS
AND PROFESSOR OF RADIOLOGY AT
THE UNIVERSITY OF PENNSYLVANIA.
HE WILL PRESENT IMAGING
APPROACHES AND THEIR
APPLICATIONS IN THE CLINICKING.
THE TITLE OF HIS TALK IS
"LYMPHATIC ANATOMICAL VARIANTS
AS A DISEASE MECHANISM, THE
IMPORTANCE OF ANATOMICAL
MAPPING.
THANK YOU MAX AND THANK YOU ALL.
>> THANK YOU, A LOT, ANDREA.
YOU CAN SEE MY SLIDES HERE.
>> YES, LOOKS GREAT.
>> THANK YOU, A LOT.
IT'S A GREAT HONOR TO BE HERE
AND SECOND YEAR I PARTICIPATED
IN NIH WORKSHOP AND IT'S REALLY
AMAZING TO HAVE DONE ALL THESE
THINGS.
SO WE TALK, I TALK ABOUT CENTER
OF.
IT MEANS EVERYTHING BUT
EXTREMITIES.
THE CENTRAL LYMPHATICS HAVE BEEN
A KNOWN FOR MANY YEARS BECAUSE
IT'S VERY, VERY HARD TO SEE
THEM.
IT'S HARD TO UNDERSTAND THEIR
PATHOLOGY OF THE CENTRAL
LYMPHATIC SYSTEM BECAUSE WE
DIDN'T HAVE A GOOD IMAGING.
OF COURSE, WHEN YOU TALK ABOUT
IT'S AVAILABLE TO SEE THE PEOPLE
AND YOU CAN ADDRESS IT BUT
CENTRAL NOT THAT MUCH.
CENTRAL LYMPHATIC ANATOMY
EXTREMELY COMPLEX.
THERE'S ALSO EXTREME VARIABILITY
IN THIS SYSTEM.
AND IT'S REALLY DIFFICULT TO
INVESTIGATE IN CLINICAL SETTINGS
BECAUSE THE SIZE IS SMALL AND
IT'S HARD TO INTRODUCE CONTRAST.
SO THIS IS JUST TO SHOW THE
DIFFERENCE IN COMPLEXITY OF THE
LYMPHATIC SYSTEM AND THE
VASCULAR SYSTEM AND IT'S ALL
DRUGS OF COURSE.
THIS VARIATION OF THE LYMPHATIC
HAS BEEN KNOWN FOR MANY YEARS
AND THIS IS A PAPER FROM 1915 BY
Dr. DAVIS, WHO DID THIS
STATISTICAL STUDY OF THE MAN ON
120 AND HE DISCOVERED NINE TYPES
OF THORACIC TO MOST COLON TYPE
TWO AND SIX THE ONLY 40% OF THE
STUDY.
SO, WHY IS THIS SO COMPLEX?
BECAUSE IT'S DEVELOPED COMPLEX.
IT DEVELOPED FROM DIFFERENT
VEINS AND THEN THEY FUSED
TOGETHER AND THERE ARE MISTAKES
IN THIS FUSION CAN CAUSE THIS
VARIATION OF NORMALITY FOR
LYMPHATIC SYSTEM.
UNTIL RECENTLY, THE LYMPHATIC
SEARCH WAS BASED PRIMARILY ON
DIE SEX AND AND BECAUSE OF THE
SIZE OF OF LYMPHATIC CELLS IT'S
VERY HARD TO IDENTIFY THEM,
ALSO, THE CASTING TECHNIQUES
THAT USED FOR ANY VASCULAR HAVE
LIMITATIONS FROM LYMPHATIC
SYSTEM BECAUSE PRESENCE OF THE
VALUES THAT SOMETIMES PREVENT
PROPAGATION OF THE RAISE INTO
THE DIFFERENT AREAS OF LYMPHATIC
SYSTEM.
AND THERE'S NO UNDERSTANDING OF
REAL-TIME FLOW DIRECTION IN THE
LYMPHATIC SYSTEM AND
COMMUNICATION BETWEEN DIFFERENT
TYPES OF LYMPHATIC SYSTEM
BECAUSE EACH ORGAN IN THE BODY
HAS ITS OWN LYMPHATIC SYSTEM
THAT FUNCTIONS DIFFERENT AND
CREATES THE LYMPH IN A DIFFERENT
WAY.
THOSE ARE VERY, VERY IMPORTANT.
IT STARTED SEVEN OR EIGHT YEARS
AGO AND THIS IS A LIST OF
DIFFERENT TECHNIQUES THAT
STARTED WITH GEOGRAPHY AND MRI
AND AND CT AND MORE.
THIS IS A FIRST STEP.
THE FIRST INTRAANODAL
LYMPHANGIOGRAPHY.
YOU TAKE THE NEEDLE AND APPROACH
IT IN THE MASS AND INJECT
CONTRAST.
THIS IS IMAGES ON THE LEFT, THIS
IS SCOPE I CAN AND THAT'S HOW IT
LOOKS ON THE PATIENT.
YOU CAN APPLY THIS TECHNIQUE
EVERYWHERE WHERE THERE ARE REACH
LYMPHATIC TISSUE, AGAIN, GROWING
AND LYMPH NODES AND AND
SURPRISING BECAUSE LEVER PORTAL
LYMPHATIC SYSTEM ARE BIG AND YOU
CAN ACTUALLY SEE THEM AND ACCESS
THEM AND THIS IS TWO EXAMPLES OF
THE LEFT MR ON THE RIGHT ON THE
LEFT WE HAVE INJECT AND ON THE
RIGHT CONTRAST AND IT WAS
DEVELOPED FIRST AND RECENTLY WE
STARTED TO DO MORE AND MORE CT
AND IT'S MUCH EASIER FOR PEOPLE
TO DO.
LIVER, YOU PUT THE NEEDLE CLOSE
TO THE PORTAL VEIN AND IF THE
LIVER IS CO CONGESTED YOU CAN SE
THE LYMPHATIC QUITE WELL AND ADD
CROSS SECTION IMAGING TO THAT,
C.T., ROTATIONAL TC SOMETIMES
GET INFORMATION AND WE DON'T
FIND IT EXTRAORDINARILY USEFUL.
WHAT DID WE DISCOVER OVER IS
THIS SEVEN OR EIGHT YEARS.
IT'S ALL INVOLVED NORMAL
LYMPHATIC ANATOMY.
THERE ARE TWO TYPES, SOMETHING
DEVELOPED OBSTRUCTION AND
OBSTRUCTION OF THE LYMPHATIC
SYSTEM AND DEVELOPMENT OF
PATHWAYS AND USUALLY IT WAS THIS
WITH LYMPHATIC AND IT'S WORKS
QUITE WELL.
SO, THIS IS A DIFFERENT TYPE OF
LYMPHATIC VARIANTS.
WE START WITH THORACIC DUCT.
IT'S BEEN IN FOCUS OF LYMPHATIC
RESEARCH FOR MANY, MANY YEARS,
OVER 100 YEARS AND PEOPLE MANY
YEARS AGO FIGURE OUT THAT IT CAN
CAUSE DIFFERENT PROBLEMS, THIS
IS A INCOMPLETE LIST OF THE
CONDITIONS WE TREAT RIGHT NOW.
LOW AB NOM INEXTREMITY AND MORE
AND MORE.
THE SECOND ONE THAT ACTUALLY WAS
CHRONOLOGICALLY TO FIGURE OUT IS
IT CAN CAUSE BRONCHITIS AND THE
LAST ONE HERE IS LYMPHATICS AND
THE LIVER/RETROPERITON AND MORE
SO THIS IS EXAMPLE OF THE
ABNORMAL PULMONARY LYMPHATIC
FLOW ON THE LEFT AND ON THE
RIGHT YOU CAN SEE NORMAL AND ON
THE FAR-RIGHT YOU CAN SEE THIS
ABNORMAL FROM THORACIC INTO LUNG
WITH PLASTIC BRONCHITIS AND THE
SAME IDEA HERE, THIS IS
NEONATAL, THE SAME EXACT
PROCESS.
OBSTRUCTION OF THE PART OF THE
THORACIC OF FLUID IN THE LUNG
AND OF COURSE, THIS IS GEOGRAPHY
AND LUNG DISEASE AND CAN BE
CAUSED BY THIS SAME PROCESS.
LIVER, WE PERFORM MORE AND MORE
OF THOSE.
USUALLY WHEN WE PUT THE NEEDLE
IN THE LIVER AND INJECT IN
NORMAL SITUATIONS, YOU CAN SEE
THAT THERE ARE COMMUNICATIONS
THORACIC WITH THE DUCT.
IT'S ACTUALLY BECAUSE PRIMARILY
WE SEE ABNORMAL SO IT'S ONE OR
TWO NORMAL CASES I HAVE.
BUT, I'LL SHOW YOU SOME ABNORMAL
BUT WHAT IS IMPORTANT TO
UNDERSTAND IS THIS PART OF THE
UPPER ABDOMEN.
THE LYMPHATIC PART OF THE UPPER
ABDOMEN.
IT'S ACTUALLY THE CROSS ROADS
THE MOST BUSIEST PART OF THE
LYMPHATIC SYSTEM WHERE ALL
LYMPHATIC VESSELS MEET.
FROM LIVER, PANCREAS, SPLEEN,
KIDNEYS, EVERYTHING COMES THERE
SO THIS STUDY Dr. DEKI FROM
JAPAN DID THIS DIE SECKION AND
DEMONSTRATED HOW COMPLEX IT IS.
YOU CAN IMAGINE, IF YOU HAVE A
LYMPHATIC SYSTEM UNDER CERTAIN
STRESS LIKE HEART FAILURE, IF
THIS LYMPHATIC VESSEL COMES
CLOSE TO THE SURFACE OF THE THEY
CAN LEAK AND CAUSE PROTEIN.
IN OTHER CASES, THIS IS A SIGN
OF HEART FAILURE WHERE THIS
ABNORMAL FLOW OF THE LYMPH FROM
THE CONGESTED LIVER INTO THAT
CAUSE.
THE NEXT ONE IS PROBABLY THE
FOCUSED ON A LOT RIGHT NOW ON
THIS.
WE DISCARD MULTIPLE DISEASES
THAT THESE OBSTRUCTIONS.
AND AGAIN, IT'S HIGHLY VARIABLE
AND IN A FOCUS OF THE LYMPHATIC
RESEARCH FOR AGAIN, AT LEAST 100
YEARS, AND YOU CAN SEE THIS IS A
PAPER FROM 1977 WHERE CADAVER
STUDY SHOWS THE DIFFERENT
VARIANTS OF THE COMMUNICATION
WITH THORACIC AND VENUS SYSTEM
AND OF COURSE, THIS
COMMUNICATION, OF NO
COMMUNICATION CAN CAUSE VARIETY
OF THE PROBLEMS UPSTREAM.
THIS IS NOT A STUDY FROM NEW
ZEALAND, RECENTLY FROM 2020.
THIS IS HOW NORMAL THORACIC DUCT
LOOKS LIKE.
SINGLE AND DOZE INTO THE VEIN.
THIS IS A CHILD WITH HIGH TROPES
AND IT'S NOT ABSENT AND IT'S
PRACTICALLY ABSENT.
THIS IS ANOTHER CONDITION.
YOU CAN SEE THAT INSTEAD OF NICE
AND CURVE EMPTY INSIDE THE VEIN
IS ACTUAL LOW VERY, VERY
TORTUROUS AND IT CREATES THE
OBSTRUCTION OF THORACIC DUCT
RESULTING IN THE DEPOSITION OF
DEBRIS AND AND OPENING THIS
OBSTRUCTION RELIEF PAIN.
THE ANGLE HOW THORACIC GETS INTO
THE VEIN CAUSED THE PATIENT POST
RIVER TRANSPLANT AND THIS IS
LIVER TRANSPLANT AGAIN YOU CAN
SEE THAT INSTEAD OF ONE THORACIC
DUCT THERE ARE MULTIPLE BRANCHES
AND THIS RESULT AND RESOLUTION
OF THE SYSTEMS.
SO A MAT K ANATOMY IS THE ANSWE.
THERE'S LYMPHATIC FLOW AS WELL
BUT I'M NOT TALKING ABOUT THAT.
BECAUSE WHAT WE ALSO FOUND IS
THAT THE AMOUNT OF LYMPHATIC
FLOW IN THE BODY CAN CAUSE
CERTAIN OVERFLOW.
THIS IS OUTSIDE THE SCOPE OF
THIS DOCK.
A YEAR AGO, I'VE BEEN CONTACTED
BY THE HEART DOCTOR AND THEY
SUGGESTED TO START THE NEW
NETTING OF THE THE LYMPHATIC
SYSTEM AS PART OF HUBMAP AND IT
STARTS WITH THIS TO CREATE A
LYMPHATIC VESSEL MAPPING.
WE SCRATCH OUR HEADS AND WE
DISCOVERED THIS OLD BOOK FROM
1938 AND DECIDED TO SUMMARIZE
THIS BOOK THAT IS PRIMARILY TEXT
AND NEW IMAGES INTO THIS MAPPING
AND OUR WORK WAS VERY FORTUNATE
TO WORK WITH ROBIN WHO SPENT
DAYS AND DAYS CATEGORIZING ALL
THIS LYMPHATIC SYSTEM AND THAT'S
HOW THE BOOK PRESENTS.
YOU CAN SEE WE DID A MAP AND OUR
JOKE WAS TO PRIMARILY SUMMARIZE
THE CENTRAL LYMPHATIC SYSTEM AND
A DIFFERENT LYMPHATIC SYSTEM.
SO WHY IT'S IMPORTANT BECAUSE
IT'S PROVIDED A NORMAL
ANATOMICAL REFERENCES AND IN THE
FUTURE PROVIDE THE LEAST OF THE
LYMPHATIC SYSTEM AND SO FOR
EXAMPLE, THIS IS PROTEIN AND YOU
CAN GO TO THE MAP AND THEY
IMMEDIATELY YOU CAN SEE THE
CONNECTION BETWEEN LIVER,
LYMPHATIC AND INTESTINAL
LYMPHATIC.
THIS IS AN EXAMPLE OF NO ONE
THAT WHERE THAT.
>> WE CAN SEE THAT THIS IS LEAK
OF THE LIVER LYMPHATIC INTO LUNG
AND THE BRON KAI AND IMMEDIATELY
WE CAN PHRASE THIS COMMUNICATION
ON THIS MAP AND THIS IS JUST
FROM THE SAME REGULAR BOOKS.
SO, WE COMPILED THE CURRENT
KNOWLEDGE OF LYMPHATIC ANATOMY
FROM ALL SOURCES AND USING THIS
CURRENT IMAGING TECHNOLOGY
PROVIDED TO UPDATE OF EXISTING
KNOWLEDGE AND OF COURSE, WE NEED
TO CONTINUE IMAGING TECHNIQUES
AND HUBMAP IS THE TECHNIQUE AND
WE'RE FORTUNATE TO TALK ABOUT
THAT AND WE'VE BEEN AWARDED A
GRANT FROM NIH TO START THIS
LYMPHATIC PROGRAM AND OF COURSE,
THERE'S A LOT OF PEOPLE INVOLVED
IN THIS PROJECT.
IT'S JUST A SMALL GROUP OF THE
PEOPLE BUT THERE'S MANY, MANY
MORE AND THANK YOU, VERY MUCH
FOR YOUR ATTENTION.
WONDERFUL.
THANK YOU SO MUCH, MAX.
WE'LL HOLD YOUR QUESTIONS TO THE
END.
NOW WE'RE READY FOR DID YOAV
DORI.
OUR SECOND SPEAKER IS Dr. DORI
THE DIRECTOR THE JILL AND MARK
FISHMAN CENTER FOR LYMPHATIC
RESEARCH AT CHILDREN'S HOSPITAL
OF PHILADELPHIA Dr. DORY WILL
OUTLINE NOVEL APPROACHES FOR
CLINICAL IMAGING OF THE HUMAN
LYMPHATIC SYSTEM AND THE TITLE
OF HIS TALK IS LYMPHATIC FLOW
DISORDERS AND SYSTEMIC DISEASE
NEW INSIGHTS FROM NOVEL IMAGING
TECHNIQUES AND NEW TREATMENT
OPTIONS.
THANK YOU SO MUCH, YOAV.
>> THANK YOU, CAN EVERYBODY HEAR
ME?
CAN YOU HEAR ME WELL?
>> YES.
>> AWESOME.
GOOD.
EXCELLENT TALK THERE MAX, THAT
WAS GREAT, GREAT WORK AS ALWAYS.
SO FIRST OF ALL I'D LIKE TO
THANK THE ORGANIZERS, AGAIN,
THIS IS AMAZING CONFERENCE AND
THERE'S SO MANY QUESTIONS THAT
THIS KIND OF CONFERENCE OPENS.
I REALLY DO HAVE ANYTHING TO
DISCLOSE EXCEPT TO SAY I HOPE
THE WORK WE DO IS A FORCE FOR
FOOD AND I'M PART OF THAT
MOVEMENT AND HOPEFULLY THAT WILL
CONTINUE.
I'M GOING TO ACTUALLY CONTINUE
TO THE PREVIOUS CONVERSATION AND
WITH A LITTLE BIT OF A DIFFERENT
ANGLE.
SO, YOU KNOW, WE HAVE A LOT OF
PATIENTS THAT WE'RE DEALING WITH
NOW WHO HAVE ORGAN DYSFUNCTION
THAT ULTIMATELY LEADS TO
LYMPHATIC DYSFUNCTION.
WE KNOW THAT LYMPHATIC
DYSFUNCTION CAN LEAD TO ORGAN
DYSFUNCTION AND THE QUESTION IS
WHAT IS THE RELATIONSHIP BETWEEN
THESE WHO THINGS?
AND UNFORTUNATELY, FIRST OF ALL,
THERE'S A LOT UNKNOWN ABOUT IT
BECAUSE CENTRAL LYMPHATIC
IMAGING WAS NOT ALWAYS
AVAILABLE.
EVEN WITH NO IMAGING, IF YOU
KNOW THE ANATOMICAL CONNECTIONS
THERE'S A LOT ABOUT THESE
DISEASES THAT ARE NOT KNOWN.
THERE ARE MANY STEPS ON THE WAY.
SOMETIMES, YOU KNOW, ABNORMAL
THINGS THAT ARE CURING NOT
ALWAYS DIRECTLY LINKED TO EACH
O. AND THEOTHERAND THERE'S A LOD
HOW THIS WORKS.
IF YOU ARE DEAL WITH A LYMPHATIC
SICK YOU LATORRE SYSTEM, YOU
NEED TO CHARACTERIZE BUT YOU
HAVE TO BE ABLE TO CHARACTERIZE
FLOW AND YOU HAVE TO BE ABLE TO
CHARACTERIZE THE FACTORS THAT
ARE EFFECTING THESE THINGS
BECAUSE WITHOUT DOING THAT, YOU
WILL NOT BE ABLE TO CHARACTERIZE
THE DISEASES THAT YOU ARE
DEALING WITH.
I MEAN, JUST LIKE THIS IS WHAT
IS THE APPROACH THAT WE'VE TAKEN
ON THE CARDIOVASCULAR SIZE AND
THE SAME EXACT APPROACH IS ON
THE LYMPHATIC SIDE.
MAX SHOWED ALREADY THE TECHNIQUE
WE DEVELOPED HERE OF DYNAMIC
CONTRAST AND SO THIS IS REALLY
GOOD.
THIS IS MR DYNAMIC CONTRAST AND
THE GREATNESS ABOUT THIS, IT
ALLOWED US FOR THE FIRST TIME TO
SEE ANATOMY AND ALSO TO SEE HOW
THE FLOW PATTERNS ARE OCCURRING
AND THIS IS GOOD FOR LOOKING AT
SOME OF THE LUNG LYMPHATIC
STUFF.
IT REALLY DOESN'T SHOW US VERY
WELL WHAT HAPPENS IN SOME OF THE
OTHER IMPORTANT STREAMS.
UNFORTUNATELY, THERE'S REALLY NO
TECHNIQUE THAT IS AS GOOD AS MRI
AND SHOWING US DIS STAAL
CONNECTIONS OF DIFFERENT STREAMS
AND HOW THINGS ARE
INTERCONNECTED TO EACH OTHER.
WE NOW DEVELOPED THE TECHNIQUES
TO IMAGE ALL THE OTHER
COMPARTMENTS AND YOU KNOW ONE OF
THE IMPORTANT ONCE IS THE LIVER.
SO SHOWN OVER HERE WITH NORMAL
LOOKS LIKE AND IT IS JUST
INJECTION OF THE LIVER CONNECTED
TO THE RETRO PER TEE KNEEL AND
THE THORACIC DUCT GOING UP.
THE LAST STREAM THAT WAS REALLY
NOT ROUTINELY IMAGED IS REALLY
VERY HARD, YOU CAN IN SOME CASES
GET INTO LYMPH NODES IN THE MESS
TARRY BUT IT'S VERY RARE AND
IT'S INTERMITTENT AND WE NOW DO
IT ROUTINE AND IN OUR PATIENTS
AND INTRA HIP ATTIC, WE
PUBLISHED ABOUT SOME OF THESE
CONNECTIONS OF RIVER CONNECTING
TO DIFFERENT THINGS AND JUST
PUBLISHED A PAPER ABOUT THAT AND
HOW IT RELATES TO DYSFUNCTION OF
THESE DIFFERENT ORGANS AND THE
DIFFERENT DISEASES WE SEE AND
INTERNET THIS IS THE LAST ONE
THAT KIND OF SOLVES THE WHOLE
REAL MAINSTREAMS THAT ARE COMING
OUT OF THE CENTRAL LYMPHATIC
SYSTEM BECAUSE IT GIVES US THE
LONG ORGANS AND THIS IS ROUTINE
IMAGING AND WE'VE DONE MANY,
MANY CASES WITH THIS AND CLOSE
TO 100 AND THIS IS WHAT NORMAL
LOOKS LIKE SO THIS IS MESS TARRY
GOING UP AND CONNECTING TO THE
LEFT.
IN ADDITION TO THE ANATOMY AND
THE FLOW, AS I SAID, WE NEED TO
UNDERSTAND WHAT IS GOING ON AS
FAR AS THE DYNAMICS, AGAIN, I'M
A CARDIOLOGIST SO UNDERSTANDING
PRESSURE IS WHAT WE DO ROUTINELY
AND WE NEED TO BE ABLE TO
CHARACTERIZE THAT AND WE'VE
STARTED NOW CHARACTERIZING AND
REPORTING SOME OF THAT AND THIS
IS A PAPER THAT WE JUST
PUBLISHED WITH A COLLABORATION
IN DENMARK ABOUT THE SPONTANEOUS
CONTRACTIONS OF THE THORACIC
DUCT AND ANOTHER PAPER THAT IS
JUST GETTING PUBLISHED ABOUT
RESPONSE OF THORACIC DUCT TO
CERTAIN DIM STIMULI AND YOU CAN
SEE THAT PLEASURE INSIDE THE
THORACIC DUCT CAN RISE ABRUPTLY
AND STAY ELEVATED UP TO
40 MILLIMETERS OF MERCURY AND
WHAT DOES THIS MEAN?
IT HAS IMPLICATIONS AND THESE
ARE THINGS THAT WE ARE CURRENTLY
LEARNING.
THERE ARE MANY KINDS OF
INTERVENTIONS THAT WE DO INSIDE
THE LYMPHATIC DUCT.
SOME INCLUDES THINGS AND SOME
ARE DECOMPRESS THINGS AND WE
PUBLISHED ABOUT SURGICAL
DECOMPRESSION PROCEDURES.
THOSE WORKED BUT WE HAVE TO BE
ABLE TO UNDERSTAND BASED ON THE
SUBSTRATE WE'RE DEALING WITH
WHICH OF THESE IS GOING TO WORK
BETTER.
SO I WON'T BE ABLE TO TALK ABOUT
OBVIOUSLY ALL THE ORGANS AND
JUST DEALING WITH LET'S SAY LUNG
DISEASE AND WE'LL TAKE THAT AS
AN EXAMPLE AND WE HAVE MEET OWE
NATNEONATAL LUNGDISEASE AND IT E
RESPIRATORY SUPPORT.
SOME OF THESE BABIES STARTS A
CYCLE OF INCREASE INEXTRA
THORACIC PRESSURE, INCREASED CDP
AND THOSE TWO LEAD TO LYMPHATIC
DYSFUNCTION AND AGAIN WE HAVE
BABIES WITH HIGH CVP OR WHO
DON'T DO THIS BUT SOME DO THIS
AND WHEN LYMPHATIC DYSFUNCTION
OCCURS, THEY DEVELOP INFLATIONS
AND OTHER THINGS, TISSUE EDEMA,
AND THIS ULTIMATELY LEADS TO
WORSENING OF THE RESPIRATORY AND
THEY JUST START CIRCLING THE
DRAIN AND MOST OF THEM IT LEADS
TO DEATH.
BUT WE CAN INTERVEN AND STOP
THIS PSYCHE MANY USING VERY
SPECIAL INTERVENTIONS IS ALL
THE CHANNELS ARE EVERYWHERE BUT
YOU CAN SEE HERE THAT THE
THORACIC DUCT IS EXTRAORDINARY
DIE A LATED AND SHOULD BE
DRAINING TO THE VEIN.
INSTEAD IT'S FLOWING INTO THIS
CHILD'S HEAD AND THE CHILD'S
HEAD IS ENORMOUS AND YOU CAN SEE
WHEN WE ALTER THE RESPIRATORY
STUFF, SO WE LOWER SO THIS
SHOULD BE NON PUBLICATION
HOPEFULLY SOL SOON.
THIS IS CAUSING THE DOUG DUCT NO
DRAIN.
THEY HAVE A MULTI COMPORTMENT
LYMPHATIC SYSTEM.
DIFFERENT PARTS OF THE LYMPH ARE
FAILING.
SOMETHING IS WRONG THAT IS
CHALLENGING THEIR LYMPH SYSTEM
AND ONE OF THEM IS THIS
FUNCTIONAL THORACIC OBSTRUCTION
AND THIS IS WHAT LUNG DISEASE
DOES AND IT'S OBSTRUCTING THE
OUTLET.
BUT IT DOESN'T WHEN IT DOES
THAT, IT ALTERS THE FLOW OF THE
DIFFERENT SYSTEMS SO HERE IS YOU
CAN SEE EVEN THOUGH THE ACCESS
WAS GOOD THERE'S A LITTLE BIT OF
A LEAK INTO THE INTESTINE HERE
BUT IT IS NOT LIGHTING UP AT ALL
SO THERE'S NO FLOW OUT INTO THE
THORACIC DUCT WHICH IS WHAT IT
IS SUPPOSED TO DO.
AND THAT HAS IMPLICATIONS.
AND HERE IS THE IMAGING IN THIS
KID AND THE INTESTACY TINS ARE
FILLING QUICKLY SO THIS IS
SEVERE PROTEIN LOSING AND THERE
ARE CONNECTIONS FROM THE LIVER
UP INTO THE LUNG BUT AGAIN
AUTHORIZE AUCTTHORACICDUCT IS N.
AND IT LIGHTS UP THE DUCT AND
LIGHTS UP A WHOLE BUNCH OF OTHER
STUFF.
THE BLACK FLOW IN THE SKIN AND
ALL THOSE THINGS.
AND THIS IS WHAT IT LOOKS LIKE
LATER ON IN HIGHER RESOLUTION
IMAGING.
THESE FINDINGS HAVE IMPLICATIONS
BECAUSE ONE OF THE FINDINGS IN
THESE KIDS IS THEY CAN'T BE FED.
THEY CAN'T EAT.
IF THEY CONDITION DRIVEN INTO CA
PROBLEM.
THEY HAVE PROBLEM LOSING THEY
HAVE A HUGE CHANNEL GOING IN THE
SKIN AND GOING ALL OVER THE
PLACE, AND SO, THESE THINGS
MATTER ULTIMATELY WHAT IS GOING
ON IN THERE.
CLINICALLY.
TO SHOW YOU HOW WE CAN BREAK THE
CYCLE.
THIS IS A CHILD WITH SEVERE LUNG
DISEASE, ABNORMAL CENTRAL FLOW.
NO ABNORMAL VARIANT HERE JUST
FLOWING INTO THE HEAD BECAUSE IT
CAN'T DRAIN.
WE DID SEVERAL PROCEDURES ON
THIS BABY AND OBSTRUCTED THE
FLOW GOING INTO THE HEAD AND THE
CHANNEL GOING INTO THE HEAD WAS
MUCH BIGGER THAN THE NORMAL
CHANNEL THAT WAS CONNECTED TO
THE VEIN SO WE REROUTED THE FLOW
GOING INTO THE VEIN.
AS SOON AS WE DO THAT, THE
CHILD'S HEAD GOES DOWN AND EDEMA
GOES DOWN AND THE LUNG DISEASE
IS CHANGING BECAUSE THE CHILD IS
PEEP.
SO IT'S REVERSED AND THE CHILD
GETS BETTER AND WE TAKE A CHILD
FROM LIFE-THREATENING AND THEY
SURVIVE.
WE CAN DO THAT BY UNDERSTANDING
THESE DIFFERENT THINGS.
NOW, CHRONIC LUNG DISEASE, ONE
OF THE PARTS OF CHRONIC LUNG
DISEASE IS PULMONARY EDEMA SO
IT'S A LYMPHATIC DYSFUNCTION.
WE DON'T MOW MUCH ABOUT THAT IS
WHAT IS LYMPHATIC DOING EVEN IF
THEY'RE FLOWING, AND A CHILD
THAT HAS AN LUNG LIKE THAT BUT
WITH YOU KNOW THAT DOING CERTAIN
PROCEDURES AND INTERVENTIONS CAN
TAKE A CHILD WITH LUNGS LIKE
THAT TO THIS WHERE LUNG DISEASE
IMPROVES.
THE CHEST X-RAY IS NOT WET BUT
WHAT ARE THEY DOING IN THE
DIFFERENT PICTURES OVER HERE,
IT'S SOMETHING THAT WE DON'T
COMPLETELY UNDERSTAND.
LYMPH DYSFUNCTION CAN CAUSE
ORGAN DYSFUNCTION AND NO BETTER
IS THE EXAMPLES OF THESE
PATIENTS.
I KNOW PEOPLE TALKED ABOUT KLA
YESTERDAY BUT THIS IS A GIRL
WITH KLA AND WE PUBLISHED ABOUT
THIS WHO PRESENTED WITH US WITH
SEVERE PULMONARY DYSFUNCTION SO
HER FUNCTION TEST YOU CAN SEE
OVER HERE WERE HALF NORMAL AND
SHE COULD BARELY WALK A CROSS
THE ROOM.
SHE HAD TO QUIT COLLEGE.
EVERYTHING THAT WE UNDERSTOOD
ABOUT LUNG DISEASE, TURNED OUT
TO BE WRONG AND WE PUT HER ON
THE DRUG AND SHE WITHIN A FEW
WEEKS NORMALIZED HER LUNG
FUNCTION SO LUNG FUNCTION, EVEN
THROW HAD HE LIVED FOR 23 YEARS
WITH HORRIBLE LUNG FUNCTION, IT
IMMEDIATELY REVERSES.
ALL HER SYMPTOMS GO AWAY AND
THIS IS WHAT IT LOOKS LIKE.
HERE IS HER INFUSIONS AND HER CT
IS NORMAL AND CENTRAL LYMPH
SYSTEM IS NORMALIZING AND YOU
CAN SEE THAT ALL THE PRO FUSION
SHE HAD BEFORE AND WE DIDN'T DO
ANY INTERVENTIONS OTHER THAN
PUTTING HER ON A DRUG AND
REMODELING HER LYMPHATIC AND ALL
THE STUFF FLOODING THE LUNG AND
ALL THE ABNORMAL FLOW IS GONE.
HER T2MRI OF HER CHEST
NORMALIZED COMPLETELY AND THE
GIRL WHO COULD NOT WALK A CROSS
THE ROOM, RUNS A 5K MARATHON
THREE MONTHS AFTER STARTING THE
DRUG AND NOW PRACTICING FOR A
10K MARATHON, SO THINGS
COMPLETELY REVERSED.
THIS IS KIND OF A PARADIGM SHIFT
IN THE WAY WE WERE THINKING
ABOUT IT BECAUSE WE THOUGHT, YOU
KNOW, LUNG DISEASE IS BAD AND IT
GETS FIXED BUT STANA LEWDED TO
THAT BEFORE YOU KNOW, THINGS ARE
NOT EXACTLY COMPLETELY FIXED AND
NOT COMPLETELY REVERSIBLE AND I
THINK THERE'S A LOT MORE THAT WE
NEED TO DO TO UNDERSTAND.
WHAT IS REVERSIBLE AND WHAT IS
NOT AND WHAT WE CALL LUNG
DISEASE.
THERE ARE CASE WHO'S HAVE THIS
ANATOMICAL VARIANT.
THIS PULMONARY PRO FUSION STUFF.
WHEN YOU TAKE A CHILD WHO HAS
THAT EX YOU CHALLENGE THEM WITH
HEART DISEASE WHICH IS THIS KID,
THINGS GET BAD.
OBVIOUSLY THEY CAN'T HANDLE THE
FLOW THAT IS GOING TOWARDS THE
LUNG.
BUT WITHOUT HEART DISEASE, THEY
ARE ABLE TO HANDLE THE FLOW AND
WE DON'T COMPLETELY UNDERSTAND
HOW CAN THEY DO THAT.
THIS CHILD WHO HAS HEART DISEASE
ALSO WAS CALLED CHRONIC LUNG
DISEASE BUT HE DID NOT HAVE
CHRONIC LUNG DISEASE BECAUSE IF
YOU INTERVENE AND STOP THE FLOW
TO TOTHE LUNGS, THIS HAPPENED TS
CHILD SO HIS RESPIRATORY SUPPORT
NORMALIZES AND THE CHILD GETS
DISCHARGED FROM THE HOSPITAL BUT
HE HAS HEART DISEASE AND
LYMPHATIC DYSFUNCTION ULTIMATELY
DEVELOPING DYSFUNCTION AND
ULTIMATELY NEEDS A HEART
TRANSPLANT.
BUT AGAIN, THERE'S A REVERSE
ABILITY AND SOME OF WHAT WE'RE
LOOKING AT OVER NOW.
TO REALLY UNDERSTAND ALL OF
THIS, ONE THING WE NEED TO
UNDERSTAND IS THE PHENOTYPE AND
THE IMAGING HELPS US DO THAT,
RIGHT.
WE NEED TO UNDERSTAND THE
LYMPHATIC DYNAMICS, WHATEVER YOU
WANT TO CALL THEM.
WE NEED TO UNDERSTAND THE
SUBSTRATE AND THE GENOTYPE AND
THE CHANNELS DOING THAT ALLOWS
CERTAIN KIDS TO DEVELOP THIS
FUNCTION AND OTHER KIDS DO NOT
DEVELOP THIS FUNCTION.
ANDMENT MATILY WHEN WE
UNDERSTAND BOTH OF THESE WE'LL
BE ABLE TO DEVELOP THE TOOLS
THAT WILL LAW US TO TREATMENT
THESE THINGS.
WE STARTED ADDRESSING THIS
TOGETHER WITH THE SARAH WHO IS
NOW IN THE NIH, A CLOSE FRIEND
AND COLLABORATOR BY LOOKING AT
THE GENOTYPE-PHENOTYPE
CORRELATION AND SHE JUST
PUBLISHED THIS PAPER.
IF THIS IS YOUR GENE, THIS IS
WHAT YOUR ANATOMY LOOKS LOOK AND
WE CAN TAKE THIS AND TRANSLATE
IT, IF THIS IS WHAT YOUR ANATOMY
WILL LOOK WHAT ARE THE ORGAN
DYSFUNCTIONS THAT ARE GOING TO
LEAD TO DYSFUNCTION IN THIS
SYSTEM THAT ULTIMAT ULTIMATELY D
TO THE SYMPTOMS.
I'LL END BY JUST SUMMARIZING
THAT AS FAR AS GAPS AND
OPPORTUNITIES, I MEAN, THIS IS
LITERALLY ENDLESS BECAUSE
THERE'S SO MUCH WE DON'T KNOW
OVER HERE.
AGAIN, WE DON'T KNOW HOW ORGANS
ARE EFFECTING LYMPHATICS AND
WHAT ARE THE LYMPHATICS
SUBSTRATES THAT -- EVEN
LYMPHATIC SUBSTRATE, WE DON'T
UNDERSTAND EXACTLY WHAT THAT IS.
YOU KNOW.
THE SYMPTOMS MIGHT BE THE SAME.
BUT IN ONE IT MIGHT BE A WALL
PROBLEM, A PUMPING PROBLEM OR
VALVE PROBLEM AND ON THE OTHER
HAND WE NEED TO UNDERSTAND WHAT
LIMBS GET DYSFUNCTIONAL INSIDE
OF AN ORGAN SYSTEM HOW IT
EFFECTS THE ORGAN AND THAT CAN
BE REVERSIBLE AND WE NEED TO
DEVELOP BETTER TREATMENT OPTIONS
FOR THESE KIND OF PATIENTS WITH
THESE KINDS OF DISORDERS AND
I'LL END BY SAYING THANK YOU,
IT'S VERY MUCH FOR IN INVITING
ME TO THIS.
IT'S AN AWESOME CONFERENCE AND I
HOPE WE GET TO WORK TOGETHER IN
THE FUTURE.
THERE'S MANY PROJECTS THAT WE
CAN DO TOGETHER ON THIS KIND OF
STUFF SO THANK YOU.
>> THANK YOU SO MUCH, YOAV, THAT
WAS REALLY INSPIRING AND
EXCITING NEWS TO HEAR ABOUT
BREANNE A WE WILL TURN IT OVER
TO Dr. NILS GEHLENBORG OUR
THIRD SPEAKER OF THE SESSION.
AN SO HE IS SEE AT PROFESSOR AT
HARD SAD MEDICAL SCHOOL WHO
ADDITIONALLY DIRECTS THE MASTER
OF BIOMEDICAL INFORMATICS
PROGRAM.
HE VISUALIZES SINGLE CELL AND
CLINICAL TITLE AND THE TITLE OF
HIS TALK IS INGRATE TIVE
VISUALIZATION OF SPATIALLY
RESOLVED SINGLE CELL DATA AND
LYMPHATIC TISSUE.
THANK YOU, NILS.
YOU ARE STILL MUTED.
>> ALL RIGHT.
I'M NO LONGER MUTED.
APOLOGIES.
I WAS GOING TO START BY SAYING
THANK YOU VERY MUCH FOR THE
INVITATION, ANDREA AND ALL THE
OTHER ORGANIZERS WHO HAVE WORKED
VERY HARD, I THINK, ON PUTTING
TOGETHER THIS AMAZING PROGRAM
FOR THIS MEETING.
I SHOULD REALLY DISCLOSE THAT I
HAVE LITTLE IN SIGHT INTO
LYMPHATICS.
I'M A DATA VISUALIZATION EXPERT.
AND I WANT TO TELL YOU A LITTLE
BIT ABOUT DATA VISUALIZATION AND
I'M BEEN INSPIRED WHAT I HEARD
HERE YESTERDAY AND TODAY.
SO, MY TALK IS ABOUT THE
INTEGRATION TIVE VISH YOUIZATION
OF MULTI MODAL AND
SPATIALLY-RESOLVED SINGLE-CELL
DATA IN LYMPHATIC TISSUE AND I
WILL TROY TO GIVE YOU A LITTLE
BIT OF A PERSPECTIVE FROM MY
WORK IN VARIOUS CELL ATLAS
PROJECTS.
I'M PART OF THE CONSORTIUM AND I
HAVE LED THIS DEVELOPMENT OF
VISUALIZE SOFT MANY HAVE HARD
PREVIOUS TALKS AND I WAS VERY
JUST HEAR THE FIRST TALK IN THIS
SESSION AND THE PREVIOUS ONE AS
WELL AND AS WELL AS OTHER TALKS
YESTERDAY THAT ALREADY MENTIONED
MAPS SO YOU SHOULD BE FAMILIAR
WITH THAT AND SO I'M WORKING ON
THE TOOLS FOR THE CONSORTIUM AND
USES TO MAKE DATA VISUAL IN THE
PORTAL AND I'M PART OF THE THE
NETWORK AND DATA COORDINATION
CENTER AND ALSO PART OF THE SO I
HAVE DEALT WITH A LOT OF
CHALLENGES RELATED TO
VISUALIZATION OF REALLY WIDE
RANGE OF DATA TYPES AND ALSO
PARTICULARLY HAVE FOCUSED SORT
OF ON THIS ISSUE AND THIS
QUESTION OF HOW WE CAN BRING
DATA TOGETHER FROM DIFFERENT
DATA TYPES AND MAKE THAT
ACCESSIBLE TO THE COMMUNITY TO
VISUALIZATION IN A WAY THAT DOES
NOT REQUIRE ANYONE TO DOWNLOAD
SOFTWARE, DOWNLOAD DATA AND
INSTALL SOFTWARE AND LITTLELY
JUST TO A QUICK LOOK AT A
DATASET AND H AND E SLIDE OR
SOME MORE ADVANCED DATA TYPES
AND SO THIS IS SOMETHING THAT
I'VE REALLY WOULD LIKE TO SOLVE
ONE AND FOR ALL FOR THE
COMMUNITY AND THAT THE MAKE IT
DEFAULT AND EVEN JUST FOR A DATA
AND THERE ARE TOOLS HOW WE LOOK
AT GOOGLE MAPS, HOW WE'VE DONE
THAT FOR HUB MAP AND I'LL GIVE
YOU A COUPLE OF EXAMPLES OF THE
DATA THAT'S AVAILABLE AT HUB MAP
AND ALSO RELATED TO LYMPHATIC
TISSUE OF COURSE AND HOW YOU CAN
WORK WITH THAT AND HOW YOU CAN
ACCESS THAT AND HOW YOU CAN USE
OUR TOOLS.
IN OUR MAP, WE HAVE A LOT OF
DIFFERENT DATA TYPES AS YOU'VE
ALREADY HEARD.
THERE ARE MULTIPLE DIFFERENT
TECHNOLOGIES AND PROBABLY TWO OR
THROW DOZEN DIFFERENT
TECHNOLOGIES THAT ARE BEING USED
TO GENERATE SPECIAL DATA, SINGLE
CELL DATA, AND VARIOUS SCALES
BUT IT GOES DOWN TO SINGLE CELL
RESOLUTION, OF COURSE.
AND SO THAT POSED A CHALLENGE IN
TERMS OF DATA VISUALIZATION AND
WEB BASED DATA VISUALIZATION SO
YOU CAN JUST USE YOUR WEB
BROWSER AND SO WHAT HAVE YOU
DONE THERE?
IN HUBMAP, WHAT IS IMPORTANT TO
UNDERSTAND IS SO HOW HUBMAP
LOOKS AT THE WORLD OF LIKE THIS
CONCEPT OF CELL ATLAS AND THERE
ARE TWO PARTS TWO MAJOR PARTS TO
IT CONTAINS KNOWLEDGE
ABOUTORSANCE, TISSUE, CELL TYPES
AND STRUCTURES, FUNCTIONAL
TISSUE AND SO ON AND SO FOURTH.
CERTAIN DATA TYPES AND LIKE
EVERYONE WHICH ALLOWS YOU AND
OTHERS TO TAKE THESE DATASETS
AND RUN ANALYSIS KNOWING THAT
THE DATA HAS BEEN PRE PROCESSED
ACCORDINGLY AND THERE ARE FIRST
VISUALIZATIONS IN THE DATA
PORTAL AS WELL AND MANY, MANY
OTHER FEATURES.
I DON'T WANT TO GO INTO TOO MUCH
DETAIL MERE BECAUSE THIS DATA
POOL IS VERY COMPREHENSIVE AND I
DO WANT TO TELL YOU A LITTLE BIT
MORE ABOUT THE ATLAS THOUGH.
ON THE ATLAS SIDE, THERE'S A
COMMON COORDINATE FRAMEWORK USED
TO PUT DATASETS IN RELATION TO
EACH OTHER WITHIN THE HUMAN
BODY.
THIS COMMON FRAMEWORK IS USED TO
DESCRIBE REALLY HOW DATASETS AND
SAMPLES AND TISSUES THAT ARE
BEING STUDIED ARE PLACED IN THE
BODY AND HOW TO RELATE IT.
THERE'S IN DEED SOMETHING CALLED
A SPACIAL OR REGISTRATION USER
INTERFACE WHERE YOU CAN PLACE
DATA SUBMITTERS WOULD PLACE
TISSUE SAMPLES IN THE ORGANS
WHERE THEY WERE TAKING FROM SO
THAT SOMEONE PULLING IN THE
DATASETS THEY CAN FIGURE OUT
WHAT PART OF THE ORGAN WAS
STUDIED HERE AND SOMETHING IS
CALLED ACT PLUS B TABLES AND
CELL TIME AND BIOMARKER TABLES
THAT DESCRIBE WHICH KIND OF
BIOMARKERS ARE KNOWN TO DESCRIBE
CERTAIN TISSUES WITHIN AN ORGAN.
AND HOW CELL TYPES CAN BE
CHARACTERIZED.
AND, AGAIN, THERE'S A LOT MORE
TO THAT BUT THIS IS SORT OF JUST
A HIGH-LEVEL AND WE ARE ALSO
WORKING VERY ACTIVELY ON
BRINGING ALL OF THIS INFORMATION
TOGETHER AND SO THE DATA SHOULD
BE CONNECTED TO THE KNOWLEDGE SO
THAT THE DATA CAN BE USED SORT
OF AS SUPPORTING EVIDENCE FOR
KNOWLEDGE IN THE ATLAS BUT YOU
CAN NAVIGATE FROM THE ATLAS TO
DATASETS FOR EXAMPLE IF YOU ARE
INTERESTED IN A CERTAIN CELL
TYPES YOU CAN RETRIEVE DATASETS
OR PARTICULAR CELL TYPES OR OF A
CERTAIN TISSUE LIKE LYMPH NODE
OR SOMETHING LIKE THAT.
SO THIS COMBINED INTERPHASE WILL
ALLOW YOU TO ANSWER QUESTIONS ON
WHAT CELL TIMES ARE PRESENT AND
WHAT IS THE SPECIAL
ORGANIZATIONAL LOOK LIKE OF
CERTAIN TISSUES AND ALSO AGAIN
AS I SAID TO HAVE SUPPORTING
EVIDENCE UNDERLYING THE ATLAS
INFORMATION AND A MEASURE OF HOW
RELIABLE AND THE INFORMATION IS
THAT IS BEING AND I WANT TO TELL
YOU MORE ABOUT WHAT WE'RE DOING
THERE IN TERMS OF SUPPORTING
SCIENTISTS IN ANSWERING
QUESTIONS THAT THEY COME AND
BRING TO THE DATA PORT SO WE
WANT TO HELP DELIVER INSIDE AND
WE WANT TO MINIMIZE THE EFFORTS
AND NEEDS TO GO INTO GENERATING
THESE INSIGHTS.
AND SO, WE'RE DOING THIS
PRIMARILY THROUGH PROVIDING DATA
VISUALIZATION TOOLS THAT I'LL
TALK MORE ABOUT IN A MOMENT BUT
THEY'RE ALSO SOME FEATURES
COMING INTO THE DATA PORTAL AND
THEY'RE NOT RELEASED AND A TASTE
OF WHAT IS TO COME AND SO WE
HAVE TOOLS IN THE WORK THAT
ALLOWS YOU TO IN CERTAIN TYPES
AND WE'RE WORKING ON INGRA TIVE
DATA ANALYSIS TOOLS THAT WOULD
BE AVAILABLE DIRECTLY THROUGH
THE DATA PORTAL THAT YOU COULD
RUN IN THE WEB BROWSER.
THE MINIMIZE THE EFFORTS BY
BRINGING ALL THE TOOLS AND THE
DATA INTO THE WEB BROWSER TO
MAKE IT AS EASY AS POSSIBLE FOR
ANYONE TO START INTERACTING WITH
THE DATA.
THAT IS OUR MODEL TO MAXIMIZE BY
MINUTE MISSING THE NUMBERS OF
CLICKS THAT ARE REQUIRED TO TAKE
A ACTION.
SO, HERE ARE TOOLS TO DELIVERING
AND HERE ARE EXAMPLES THAT YOU
WILL SEE AND HOPEFULLY YOU CAN
SEE THE ANIMATIONS HERE.
THERE ARE MANY, MANY DIFFERENT
TYPES OF VISUALIZATIONS WE
SUPPORT AND ALL OF THEM USED THE
SAME VISUALIZATION FRAMEWORK
CALLED THE TEST.
WE HAVE SORT OF THESE
INTEGRATION TIVE MULTI MODAL
IMAGING DATASETS AND SUCH AS
THIS ONE AND THIS IS A DATASET
DONE ON LYMPH NODE.
WE HAVE A TISSUE VEER.
WE ARE CONTROL ANY CHANNEL
SETTINGS FOR THIS MULTI PLEX
DATASET AND WE CAN ALSO OVER LAY
THESE TISSUE SPICES WITH CELL
SEGMENTATIONS AND THEN SHOW
QUANTIFICATIONS FOR THESE
DIFFERENT CELL TYPES SO WE CAN
TURN IT OFF AND INTERACT WITH
THIS.
YOU SEE THE EMBEDDING AND THE
PLOT ON THE RIGHT THERE'S A HEAT
MAP VIEW WE CAN CHANGE WHICH
MARKERS WE WANT TO OVER LAYER
WHAT CLUSTERING OR CELL TYPE
ASSIGNMENTS WE WANT TO SHOW
HERE.
ALL OF THEE FEATURES ARE
AVAILABLE IN THE BROWSER AND
THIS THING LET'S ME MOVE ON AND
I WILL SHOW YOU ANOTHER EXAMPLE.
SO HERE IS ANOTHER EXAMPLE IS
THE 3D VIEW AND THIS IS ALSO
LYMPH NODE TISSUE IN THIS CASE.
SO WE HAVE A 3D VIEW AND WE HAVE
THE SAME FEATURES AND WE CAN
TURN ON AND OFF CERTAIN CHANNELS
AND ROTATE THE TISSUE AND CHANGE
THE SETTINGS AS WE WISH AND
AGAIN IT DOESN'T REQUIRE
ANYTHING FOR THE WEB BROWSER TO
DO THIS AND WE CAN DO THIS BY
PRE PROCESSING THE DATA IN
CERTAIN WAYS SO IT'S EASY TO DO
THAT ON THE FLY WITHOUT HAVING
TOO MUCH ON ENABLING THESE
VISUALIZATIONS SO IT'S A
STANDARDIZED PROCESS AND WE CAN
OPERATE ON ALL OF THESE
DIFFERENT DATA TYPES AND YOU SEE
THERE ARE OTHER EXAMPLE HERE
THIS IS THE SPACIAL TRANCE AND
WHERE YOU CAN SEE THIS PUCK ON
THE LEFT AND CENTER VIEW ON THE
RIGHT YOU HAVE THE SAME DATA AND
OVER LAY DIFFERENT CELL TYPES
THAT WERE DETECTED IN THIS
TISSUE USING THE STANDARDIZED
PIPELINES THAT WE HAVE IT ON
MAP.
SO ALL OF THAT IS AVAILABLE TO
USERS OFF THE HUBMAP DATA
PORTAL.
THIS IS DONE THROUGH THE
FRAMEWORK CALLED THE TEST THAT
ANYONE CAN USE THAT IS OPEN
SOURCE SOFTWARE AND THERE'S A
LOT OF DOCUMENTATION AND
EXAMPLES AVAILABLE AND HOW YOU
CAN SET UP YOUR OWN
VISUALIZATIONS WITH THIS
FRAMEWORK.
AND WHAT WE'RE DOING RIGHT NOW,
THIS IS ONLY SORT OF AT THE
SINGLE DATASET LEVEL.
EVEN THOUGH THEY'RE HIGHLY
INTEGRATION TIVE, VISUALIZATIONS
AND WE CAN SUPPORT MULTI OMIC
SETS AS WELL, THOSE ARE ALL FOR
ONE SINGLE CELL.
THE SINGLE DATASET VISUALIZATION
THAT WE'RE SUPPORTING RIGHT
THOUSAND BUT WE CAN BRING IN
CLUSTERING RESULTS,
SEGMENTATION, CELL TYPE A
SENMENTS AND IT HELPS INTERPRET
THE DATA.
WHAT WE DO DO RIGHT NOW AND WHAT
WE WILL DO IN THE FUTURE IS
VISUALIZATION OF MULTIPLE
DATASETS SO YOU CAN LOOK ACROSS
CELL TYPE ABUNDANCE FOR TISSUE
RATHER THAN JUST LOOKING AT ONE
DATASET AT A TIME AND IN THE
FUTURE WE'LL SUPPORT A HIGH
LEVEL VISUALIZATION OF THE WHOLE
ATLAS.
OTHER FEATURES THAT I WANT TO
MENTION VERY BRIEFLY THAT CAN BE
USEFUL WHEN IT'S RELEASED IS
THIS CROSS DATASETS SO HERE IS
AN EXAMPLE WHERE WE CAN
BIOMARKERS SO IN THIS CASE YOU
SELECT A GENE BIOMARKER AND IN
THIS CASE WE'RE INTERESTED IN
RNA AND QUANTIFICATIONS AND
DETERMINE SORT OF SOME CUT-OFFS
FOR WHAT SHOULD BE THE LEVEL OF
EXPRESSION FOR THIS MARKER.
AND HOW MANY -- WHAT PERCENTAGE
OF CELLS IN A GIVEN DATASET
SHOULD THIS MARKER BE PRESENT
AND WE CAN RUN A QUERY AND WE
CAN SORT OF START DRILLING INTO
THAT AND VISUALIZING THE
EXPRESSION PROFILE OFF THAT
MARKER ACROSS THE CLUSTERS OR
CELL TYPES IN THAT TISSUE.
AND SO WE CAN THEN NAVIGATE
DIRECTLY TO THE DATASETS HERE
IT'S ANOTHER KIDNEY DATASET.
WE CAN THEN DO THE SAME THING
AND WE CAN LOOK AT THE
EXPRESSION MARKER SO IT'S A
QUICK WAY OF FINDING A DATASET
WITH A MARKER OF INTEREST.
AND I'M JUST TRYING TO -- IT'S
VERY INTERACTIVE AND YOU CAN
PLAY AROUND WITH THE DATA.
AGAIN, WITHOUT ANYTHING, IT'S
JUST A COUPLE OF CLICKS TO GET
TO THESE KIND OF FEATURES.
IN THE FUTURE, WE WILL ALSO WANT
TO PROVIDE SUPPORT FOR
COMPUTATIONAL ANNALISTS AND
BIOLOGISTS AND OTHER PEOPLE WHO
WRITE SCRIPTS TO ANALYZE DATA TO
RUN CODE DIRECTLY BY USING WHAT
THOSE OF YOU WHO ARE FAMILIAR
WITH THAT, JUPYTER NOTEBOOKS AND
THAT CAN REALLY ALLOW YOU TO NOT
ONLY USE THE STANDARD FEATURES
BUILT INTO THE HUB MAP PORTAL
INTERFACE AND RUN YOUR OWN
ALGORITHMS SO YOU CAN RUN A
QUERY, FOR EXAMPLE AND YOU CAN
QUERY THE METADATA OF THE
DATASETS AND CREATE YOUR
VISUALIZATIONS ON THE FLY AND
DOWNLOAD NOTEBOOKS THAT CONTAINS
A SAMPLE CODE TO ALLOW YOU TO
RUN ANALYSIS AND WE CAN DOWNLOAD
THESE VISUALIZATIONS WHICH CAN
ALSO BE EMBEDDED DIRECTLY INTO
JUPYTER NOTEBOOKS.
FUR A COMPUTATIONAL ANNALIST AND
YOU WONDER HOW TO ANALYZE YOUR
SINGLE CELL DATA WITH A TOOL CAN
YOU DO THIS AND THIS IS AN
EXAMPLE INTO THE JUPITER
NOTEBOOK AND LAUNCH IT OR THE
VISUALIZATION IN THE NOTEBOOK
AND INTERACT WITH T I'M RUNNING
OUT OF TIME SO I WANT TO TRY TO
WRAP THIS UP.
THESE FEATURES WILL BE AVAILABLE
DIRECTLY IN THE PORTAL WHERE YOU
CAN RUN AN EX CUTE THE NOTEBOOKS
WITHOUT EVEN DOWNLOADING THEM
EVENTUALLY, THAT'S COMING UP
SOON.
WE'RE CLOSE TO RELEASING THIS
FEWTURE AND THIS IS BUILT INTO
THE HUB MAP PORTAL FOR THIS
PURPOSE.
I'VE TALKED ABOUT THIS AND I DO
WANT TO POINT OUT YOU KNOW, WE
HAVE ON THE HOME PAGE, THE DATA
TYPES WE HAVE AVAILABLE AND
THERE'S QUITE A BIT OF LYMPHATIC
TISSUE AVAILABLE AND THE DON'T
FROM LYMPHATIC TISSUES THAT YOU
CAN ACT AS A SINGLE CELL IMAGINF
THOUGHTS ON CHALLENGES IN THESE
SPACE.
THESE ARE DIFFERENT FROM WHAT
OTHER PEOPLE HAVE MENTIONED.
TO ME, THE CHALLENGES FALL INTO
THREE CATEGORIES.
SOCIOLOGICAL RELATED TO HOW
USERS DO RESEARCH AND HOW WE
ESSENTIALLY TRY TO LEARN FROM
OUR USERS WHAT KIND OF FEATURES
THEY NEED IN THOSE VISUALIZATION
TOOLS SO IT'S ONE CHALLENGE FOR
US.
WE NEED TO DO USER RESEARCH AND
SINCE EVERY SCIENTIST HAS THEIR
OWN PROBLEM AND NICHE THEY'RE
TRYING TO SOLVE, MEDICINE IS
CHALLENGING BECAUSE WE NEED TO
TALK TO A LOT OF PEOPLE TO
FIGURE OUT WHAT IS FUNCTIONALITY
FOR THESE VISUALIZATION TOOLS.
THERE ARE CHALLENGES RELATED TO
NECK KNOWLEDGES AND DATA FORMAT
AND EVERYONE WILL BE FAMILIAR
WITH THOSE AND MAYBE FOR PEOPLE
WHO ARE WORKING WITH IMAGING
DATA IT'S BEEN SOLVED AND FOR
MOST OF THE OTHER DATA
MORTALITIES THIS IS STILL AN
OPEN QUESTION OF THE STANDARD
FORMATS AND HU T HOW THEY WORK.
SCIENTISTS TRY TO ANSWER UNIQUE
QUESTIONS AND IT MAKES IT HARD
TO BUILD GENERALIZED TOOLS THAT
WORK FOR EVERYONE.
THERE ARE GREAT OPPORTUNITIES
AND I THINK THERE'S ALREADY ON
GOING EFFORTS FOR PEOPLE LIKE ME
AND OTHER COMPUTATIONAL FOLKS TO
WORK TOGETHER ON IDENTIFYING
COMMON CHALLENGES ACROSS THESE
EFFORTS AND BUILD SOLUTIONS FOR
THAT AND I THINK THIS COMMUNITY
WILL ALSO BE ABLE TO BENEFIT OF
COURSE FROM BEST PRACTICES THAT
PROJECTS LIKE HUBMAP OR HUMAN
CELL ATLAS HAVE DEVELOPED AND
COME UP WITH THE PAST AND IF YOU
WANT TO PARTICIPATE IN THAT, I
CERTAINLY HAVE A NUMBER OF OPEN
POSITIONS IN MY LAB FOR ANYONE
WHO IS LOOKING FOR NEXT STEP IN
THEIR CAREER.
THANK YOU VERY MUCH.
APOLOGIES FOR GOING OVER TIME.
>> THANK YOU SO MUCH, NILS.
YEAH, WE'LL HOLD OUR QUESTIONS
TO THE END BUT I'M GRATEFUL FOR
THE LOVE LETTER FOR HUBMAP AND
DATA SCIENCE.
OUR LAST AND FINAL SPEAK OF THE
SYMPOSIUM IS Dr. HELEN
BENVENISTE.
SO, COME ON DOWN, YOU CAN GET
YOUR SLIDES CUED UP.
SHE'S A PROFESSOR OF
ANESTHESIOLOGY AT YALE AND
INCLUDING THE DEVELOPMENT OF
METHODOLOGIES TO EXAM THE WASTE
REMOVE PROCESS IN THE BRAIN.
THE TITLE IS 3D IMAGING FLUID
AND WASTE CLEARING FROM BRAIN
AND EXPERIMENTAL MODELS OF
IMPAIRED LYMPHATIC SYSTEM.
THANK YOU AND WELCOME.
>> HELLO AND THANK YOU FOR IN
INVITING ME TO THIS INTRIGUING
WORKSHOP AND I ALSO WANT TO
CONFESS THAT I'M A NEWCOMER TO
THE FIELD OF THE LYMPHATICS BUT
I'VE BEEN DARING MYSELF TO KEEP
OPEN THE BARRIER AND THIS IS
SOME OF THE DATA I WILL BE
TALKING TO YOU ABOUT TODAY.
I WANT TO ACKNOWLEDGE SUPPORT
FROM THE NIH, THE BRAIN ENTRY
EXIST CONSORTIUM AND SUPPORTED
BY THE ALZHEIMER'S FOUNDATION
AND ALSO (INAUDIBLE) FOUNDATION.
THERE'S A LOT OF NEW KNOWLEDGE
OF HOW THE BRAIN AND FLUID AND
CONNECT TO THE LYMPHATIC SYSTEM
HAVE EMERGED AND MAPS OF THE
LYMPHATICS AND THE DRAINAGE
PATHWAYS TO THE CERVICAL LYMPH
NODES ARE BASED ON DATA FROM
RODENTS AS WELL AS FROM HUMAN
BRAIN AND I WANT TO HIGHLIGHT
THE WORK OF THE DOCTORS' LAB
THEIR WORK HAS REALLY BEEN
INSTRUMENTAL FOR PROVIDING US
THIS NEW UNDERSTANDING OF THE
DRAINAGE PATHWAY ROUTES FROM THE
BRAIN.
HOWEVER, THESE PATHWAYS HAVE TO
BE UNDERSTOOD AND DISCUSSED IN
CONNECTION WITH THE BRAIN'S
WASTE DISPOSAL SYSTEM.
THIS IS A SCHEMATIC PRESENTATION
OF WHAT WE CALL THE LYMPHATIC
MODEL OF WASTE CLEARANCE WHICH
WAS INTRODUCED ABOUT A DECADE
AGO BY.
I WANT TO HIGHLIGHT THE KEY
FEATURES OF THIS MODEL WHICH
INCLUDES INWORK FLOW OF FLUID
ALONG THE SPACE IS OF THE
PENETRATING AR TERRIER OF THE
BRAIN AND THE SPACE IS MADE UP
BY THE INNEED OF THE GLEE OWE
CELLS AND THAT WATER CHANNELS
ARE DECORATING THESE AND THEY
ARE IMPLICATED IN THE TRANSFER
OF FLUID FROM THIS SPACE AND
INTO THE FLUID AND THIS IS
PROVEN BY BLOOD FLOW AND THIS IS
MEANT BY TO SERVE AS A DRIVER
FOR HOW THE FLUID AND THE WASTE
HERE INTO THE SPACES AND HOW TO
THE LYMPHATICS.
AND I JUST WANT TO HIGHLIGHT
THAT THIS SYSTEM IS SO UNIQUE
AND THE TEAM HAVE DISCOVERED
THIS TEAM IS POLICE STATIONAL
ACTIVE DURING DEEPSLEEP.
THIS IS REALLY UNIQUE AND I
WON'T HAVE TIME TO TALK ABOUT
THIS, HOWEVER, I WANT TO POINT
OUT THIS IS NOT THE ONLY MODEL
FOR WASTE CLEARANCE AND THIS IS
A MODEL I HIGHLIGHTED AND THE
OUTFLOW AND THERE ARE OTHER
MODELS AND YOU WANT TO HIGHLIGHT
THE MIXING MODEL WHICH IS I
THINK IS ALSO REALLY LOOKED AT
WHERE THEY ARE CLAIMING THAT
THERE'S NO IN THE BRAIN AND THIS
IS ALSO MOVEMENT AND EVERYTHING
IS WASTE SOLIDS ARE ACTUALLY
MOVING OUST OF THE BRAIN BY
DIFFUSION ONLY AND THE ONLY
BLOOD FLOW WE HAVE IS ON THE
SURFACE AND INTO THE SURVIVE
SPACE.
HOWEVER, BASED ON THE NEW
LITERATURE, I WOULD SAY THE
LYMPHATIC AND MIXING MODEL ARE
PROBABLY THE BETTER ONCE ALIGNED
WITH THE BIOLOGY AND SHOW HERE
IS THE MOST RECENT SCHEMATIC MAP
OF THE DUEL VINO LYMPHATIC
NETWORK AS DEPICTED IN THE MOUSE
BRAIN AND YOU CAN SEE THE DUEL
SINUS AND DECORATED WITH A
LYMPHATIC HERE AND THESE NUMBERS
HERE ON THE SURFACE HAVE SHOWN
EXACTLY WHERE THE MENINGEAL
LYMPHATIC SITES AND ARE
RECEIVING THE LYMPHATIC AND
OUTPUT AND I RECOMMEND YOU TO
READ THE POPULAR -- IT'S A
REALLY BEAUTIFUL PAPER.
I MEAN, YOU KNOW, THESE THINGS
HAVE STILL DEBATED BUT I THINK
THIS PAPER HAS REALLY
HIGHLIGHTED SOME KEY CONCEPTS
AND THIS IS WHAT WE WANT TO
IMAGE, SO IF THE LYMPHATIC
SYSTEM IS A VARIABLE AND
ACCESSIBLE, THE SPINAL FLUID HAS
TO INTERCHANGE WITH INTER TISSUE
FLUID TO TRANSPORT THE SOLUTE SO
WE CAN CALL THIS DIRTY CSF AND
IT'S HIGHLIGHTED IN THESE PAPERS
AND WE THINK THAT THAT DIRTY CSF
THAT HAS PASSED THROUGH THE
LYMPHATICS IS ACTUALLY CONNECTED
TO THE MIN WHEN THIS SYSTEM IS T
AVAILABLE, THE CSF IS
CIRCULATING BUT IT'S NOT GOING
INTO THE EGRESSING FROM OTHER
ROUTES, PROBABLY VIA THE CRANIAL
NERVES.
FOR ABOUT A DECADE, WE
INTRODUCED A WAY TO TRACK
LYMPHATIC TRANSPORT IN THE TRAI.
THERE'S A LOT OF OTHER OUT THERE
AND THIS IS THE ONE I'M GOING TO
FOCUS ON TODAY.
I USE RATS IN THE LAB BECAUSE
THEY'RE BIGGER THAN MICE AND WE
CAN ALSO DO THIS IN MICE BUT WE
HAD REALLY WORKED A LOT IN THE
RAT AND WE INJECT SMALL
MOLECULAR AND AGENTS INTO THE
CSF VIA THE AND THEN YOU CAN SEE
HERE WE CAN MAP DYNAMICALLY
THESE MOVEMENT OF THIS COLOR
COATED AND WE CAN DO THE
KINETICS OF WHAT HAPPENED IN THE
CSF AND WHAT HAPPENS IN THE
TISSUE.
NOW, AS YOU LOOK AT T. IT'S
REALLY NOT VERY INFORMATIVE AND
WE HAVE LOOKED AT VERY BEAUTIFUL
IMAGES TODAY AND FOR ME, YOU
KNOW, THIS DOESN'T REEL TELL ME
ANYTHING ABOUT THE SPEED AND THE
BAD PHYSICAL NATURE OR THE
DIRECTION SO IN COLLABORATION
WITH Dr. TENENBAUM THE
MATHEMATICIAN AT SLOAN
KETTERING, HE HAS HELPED US AND
HE HAS DEVELOPED A COMPUTATIONAL
FLUID DYNAMICS, FRAMEWORK BASED
ON REGULAR TRANSPORT THEORY
WHICH IS A COMPLEX MATHEMATICAL
ALGORITHM THAT INCLUDES TWO KEY
TRANSPORT PROCESSES AND
DIFFUSION, I WON'T GO INTO THE
MATH IT'S NOT MY FOR PAY BUT
THIS PROCESSING PIPELINE SO WE
HAVE THE DYNAMIC IMAGES AND WE
FEED IT INTO THIS ALGORITHM AND
THIS IS WORK BY Dr. CHAN FROM
Dr. TENENBAUM'S LAB AND WE CAN
GET A LOT OF METRICS OF
INFORMATION.
WE CAN GET PATH LINE OF THE
NAND WE KNOWHOW FAST THE SOL USG
AND WE CAN GET NUMBERS THAT TELL
US IF THE MOVEMENT IS ADAPTIVE
OR DIFFUSION DOMINATED SO HERE
IS AN EXAMPLE, CAN YOU SEE, THAT
THERE'S DIRECTION AND WE CAN
ALSO GET MAGNITUDE OF THE
TRANSPORT.
QUICKLY I WANT TO SAY THAT THIS
MATHEMATICAL DATA CAN BE
PRESENTED IN TWO WAYS.
IN THE I'M SWIMMING IN THE RIVER
AND YOU GET THE WHOLE PATHWAY AS
I SWIM THROUGH THE RIVER HERE IN
EULER SO THIS IS EX LOCAL,
VELOCITY FLUX, LOCALLY IN THE
RAIN OVER A TIME FRAME FROM 640
TO 160 MINUTE ACT.
I CAN ALSO STAND HERE AND LOOK
AT THE RIVER AND SEE THE
SWIMMERS MOVING BY SO WE GET THE
TIMEFRAMES AND WE CAN LOOK AT
THE DIFFERENT STEPS AND THOSE
ARE DIFFERENT AND I HAVE A LOT
OF DIFFERENT INTERPRETATIONS.
SO HERE IS AN APPLICATION OF
THIS FRAMEWORK IN A RAT MODEL OF
SEVERAL AMYLOID AND THE AMYLOID
IS DEPOSITING ALONG THE VASCULAR
HERE IN THE RAT AND THESE RATS
GETS REALLY SICK AND 12 MONTHS
AND THEY'RE START TO GET MICRO
BLEEDS AND MIMICKING THE CLINIC
DISEASE AND THIS IS A 1-YEAR-OLD
RAT AND CAN YOU SEE SEE A NICE
PATTERN OF MOVEMENT AND MOVEMENT
INTO THE LYMPHATIC SYSTEM YOU
CAN SEE ALL THESE ARROWS OVER
HERE HIGHLIGHTED THAT THEY'RE
ACTIVELY MOVING TO THE LYMPHATIC
PATHWAY.
OVER HERE, YOU CAN SEE THE
DISEASE IS CAUSING THE CSF AND
FLOW TRAJECTORY T TO BY PASS, TY
CANNOT ACCESS THE LYMPHATIC
SYSTEM, THEY ARE ACTUALLY MOVING
TOWARDS THE FACTORY AND OTHER
EGRESS ROUTES AND THE LYMPHATIC
FLUX IS GETTING REDUCED AND WE
CAN QUANTIFY THIS.
BUT WE ALSO NEED TO SEE THE
CROSS TALK TO THE LYMPHATICS AND
THIS IS WHAT I WAS SAYING I'M
VENTURING OUT OF THE BLOOD BRAIN
BARRIER ON THE OTHER SIDE AND
HERE WE HAVE DEVELOPED RADIO
FREQUENCY CALL AT THE LEVEL OF
THE NECK AND WE USE A HIGHER
MOLECULAR CONTEST AGENCY TO GET
BETTER SIGNAL TO NOISE AND THESE
ARE ABOUT TWO MILLION DOLLARS
ACROSS ONE TO TWO MILLIMETERS
ACROSS THE LYMPHATIC NODES AND
THESE ARE THE DEEP OFFIC CERVICD
I MAPPED OUT JUST WHAT HAPPENED
AT THE LEVEL OF DEEP CERVICAL.
WE INJECT IT TO THE CSF AND
AFTER AN HOUR OR 70 MINUTES,
THIS IS WHERE THE CONTRAST PEAKS
AT THE LEVEL OF DEEP CERVICAL
LYMPH NODES AND THIS IS WHERE
THE CONTRAST FROM THE BRAIN GOES
AND THERE'S VERY LITTLE SPILL
OVER TO THE SUPERFICIAL NODES
AND THIS HAS BEEN CONFIRMED BY
MANY.
AND WE HAVE JUST NOW STARTED TO
EXPLORE IF WE CAN LOOK AT THESE
STREAMS GOING TO THE DEEP
CERVICAL, WHAT KIND OF BAD
PHYSICAL FORCE ARE DRIVERS THE
FLUIDS AND YOU CAN SEE IT LOOKS
LIKE AT LEAST SOME OF THE
STREAMS ALONG THE EXTERNAL OR
ARTED ARTERY INVECTIVE MOVES
TOWARDS THE DEEP CERVICAL BUT
AGAIN, THIS IS VERY EXPLORATORY.
THIS IS HOW WE HAVE APPLIED THIS
IN THE MODEL I JUST TOLD YOU
ABOUT.
IT HAS SEVERAL AMYLOID AND YOU
CAN SEE IN A NORMAL RAT PEAKS
AROUND AN HOUR TO 70 MINUTES AND
IN THE DECEASED RAT, THERE'S A
TIME DELAY AND THE MAGNITUDE --
THE DEEP CERVICALES ARE
RECEIVING DRAINING BUT IT'S
TIMELY LTIMEDELAYED AND IT'S SPD
THIS IS TELLING US THE DRAINAGE
PATTERN HAS CHANGED.
THIS IS A MODEL OF CHRONIC
HYPERTENSION AND THIS IS DATA WE
HAVE NOT PUBLISHED BUT THESE
RODENT MODELS ARE MODELS OF
SMALL DISEASE IN THE BRAIN AND
THESE RATS ARE VERY HYPERTENSION
I HAVE, WE HAVE BRAIN AGE TO THE
DEEP CERVICAL AND SPILL OVER TO
THE SUPERVISION NOTE SO.
NOW WHAT HAPPENS IF WE BLOCK
DRAINAGE TO THE LYMPH NODES,
THIS IS WORK INSPIRED BY WORK IN
Dr. KIMNESS LAB.
I WANT TO HIGHLIGHT THE DOCTORS
AND WITHOUT THEIR WORK, THIS
WOULD NOT HAVE BEEN POSSIBLE AND
WE DEVELOPED AND MODELED WHERE
WE ACTUALLY CART ARISED A LOT
LYMPHATIC THAT SEEM TO ACTUALLY
RUN INTO THE DEEP CERVICAL LYMPH
NODES AND WE TESTED THIS
INHIBITS DRAINING TO THE DEEP
CERVICAL AS YOU CAN SEE HERE SO
THE MODEL SEEMS TO WORK AND WE
LET THESE RATS SURVIVE FOR ONE
MONTH AND AGAIN WE EXPLORE THIS
AND ONE OF THE FIRST THINGS THAT
I ASKED WAS, WHETHER OR NOT THEY
DEVELOPED HYDROCEPHALUS, DO THEY
DEVELOP INTERCRANIAL PRESSURE
AND THESE ARE VERY NEW DATA AND
YES WE DO SEE AN ELEVATION OF
INTERCRANIAL PRESSURE IN THESE
RATS AND THEY DO NOT HAVE NORMAL
DRAINAGE TO THE DEEP CERVICAL
BUT THEY DO NOT BECOME HYDRO SEV
ALI AND THIS IS CORRESPONDING
OPTIMAL MASS TRANSPORT ANALYSIS
OF THE DATA AND THIS IS FROM TWO
RATS UNDERGOING SHAM SURGERY AND
THIS IS MAPS SO THIS IS TELLING
US IF THE TRANSPORT IS
DIFFUSEIVE AND IN NORMAL RATS,
THIS IS THE LEVEL OF THE BEE AN
AND THE RECESS WHERE WE HAVE A
LOT OF CSF AND THE PATTERN HERE
IS YOU SEE WHAT HAPPENS IN THE
RAT THAT HAS IMPAIRED DRAINAGE,
YOU CAN SEE WE HAVE THESE VERY,
VERY STRONG STREAMS MOVING
TOWARDS THE RECESS AND WE ARE
STILL TRYING TO UNDERSTAND THIS
AND THIS IS JUST A MOVIE SHOWING
THE SAME THING AND I AM NOT
GOING TO SHOW YOU THE SHAM, I
JUST WANT YOU TO SHOW ONE HOUR
IN THIS IT'S THE OPTIMAL MASS
TRANSPORT ANALYSIS OF THE
VELOCITY FLUX VECTORS AND
THEY'RE SCREAMING VERY RAPIDLY
AND THERE'S A HIGH MAGNITUDE
VECTORS MOVING UP TOWARDS THE
RECESS AND I JUST WANT TO SAY SO
IN SUMMARY, WHAT HAVE I TOLD
YOU?
I'VE INVOLVED YOU ABOUT THE
DYNAMIC CONTEST ENHANCED IN
MODALITY AND THE COMPUTATIONAL
FLUID ALGORITHM WE HAVE
DEVELOPED TO LOOK AT LYMPHATIC
SYSTEM.
I'VE SHOWED YOU APPLICATIONS
THAT WE CAN START TO TEASE OUT
WHAT IS HAPPENING IN THE NEW
DEGENERATIVE DISORDERS IN IN
SEVERAL SMALL VESSEL DISEASE AND
WE ARE JUST NOW STARTING TO
EXPLORE THE COUPLING BETWEEN THE
LYMPHATIC AND GLYMPHATIC SYSTEM
AND DOING THAT BY STARTING TO
BLOCK THE MAIN HOPS FOR THE
DRAINAGE AND WE'RE DOING PROFILE
UP MARKER, PROFILING IN
COLLABORATION WITH CERTAIN AND
WE ARE ALSO LOOKING AT WHAT
HAPPENED WITH KEY WASTE PROTEINS
LIKE PTAU WITH Dr. XIE.
I WANT TO THANK MY COLLABORATORS
AND YALE, THE STONY BROOK STEAM,
WITHOUT THEM WE CON INTERPRET OR
GET ALL THESE VARIABLE DATA AND
Dr. KIPNESS AND WHO IS DOING
THE OMICS ANALYSIS OF SOME OF
THE NEW STARTERS WHERE WE ARE
BLOCKING DRAINAGE.
AND GAPS NEEDS AN OPPORTUNITIES
THAT ARE MANY.
THESE ARE JUST SOME OF THEM.
BUT I THINK THE BIGGEST ONES ARE
TO UNDERSTAND THE DRIVING FORCES
OF HOW THINGS ARE ACTUALLY
MOVING FROM THE BRAIN AND OUT
AND I KNOW PEOPLE ARE SAYING IT
REACHES THE LYMPHATIC AND THE
NODES BUT CLEARLY THAT IS NOT
TRUE BECAUSE WITHOUT
UNDERSTANDING THE DRIVING
FORCES, WE ALSO WON BE ABLE TO
DEVELOP THE THERAPEUTICS AND I
ALSO WOULD VERY MUCH HIGHLIGHT
WE NEED NON-INVASIVE IMAGES
METHODS TO TRACK THE SAME THING
IN THE HUMAN BRAIN WITHOUT
CONTRAST.
THANK YOU FOR YOUR ATTENTION.
>> WOW, THANK YOU SO MUCH,
HELENE, IT WAS A BEAUTIFUL TALK.
NOW WE HAVE OUR 10-MINUTES OF
MODERATION AND WE HAVE LOTS OF
QUESTIONS SO, FOR THOSE OF YOU
WHO ARE HOSTING PANELS WHO HAVE
ASKED QUESTIONS TO EACH A. RAISE
OTHER, RAISEYOUR HAND AND I'LL .
THE FIRST QUESTION IS A PATIENTS
ON THE PANEL, CYNTHIA HUDSON.
IN THIS QUESTION IS FOR Dr.
DORI.
THANK YOU.
LET ME TROY AND FIND IT HERE.
HAVE THERE BEEN STUDIES ON THE
LONG-TERM EFFECTS OF TAKING
TRAMIGHTENAB AND THERE ARE A LOT
OF QUESTIONS.
MECHANISMS OF AVER ACTION.
WHAT DO YOU KNOW?
UNLOAD IT HERE.
THANK YOU SO MUCH AND THANK YOU,
THIN SEE CYNTHIA.
>> SO THOSE ARE ALL EXCELLENT
QUESTIONS.
THE ANSWER TO THE QUESTIONS ARE
PRETTY MUCH YOU KNOW, THAT
THERE'S A WHOLE BUNCH OF GAPS OF
KNOWLEDGE AS FAR AS -- SO WE
KNOW MECHANISMS ARE ACTION IS
IT'S A INHIBITOR.
WHAT ACTUALLY IT IS DOING, HOW
IT IS ALTERING THE LYMPH SYSTEM
WHY THINK WE COMPLETELY
UNDERSTAND THAT.
SARAH SHEPHERD FROM THE NIH WHO
WE WORKED ALL TOGETHER HAS A
GROUP, HAVE THE ANIMAL MODELS
AND ALL THOSE THINGS WHERE
THEY'RE STARTING TO DO EXACTLY
THAT TO FIGURE OUT WHAT ARE THE
FUNCTIONAL EFFECTS OF THESE
DRUGS LIKE WHAT ARE THE PATHWAYS
THEY EFFECT.
AGAIN, WHEN WE STARTED TREATING
PEOPLE AND WE DID IT FIRST FOR A
PATIENT WHO IS NOT A KLA PATIENT
BUT A CONDUCTION DISORDER WE DID
IT BASED ON FISH DATA.
WE SAW THE EFFECTS ON A FISH
DATA AND WE HAD A PATIENT WHO
WAS DYING FROM HIS DISEASE, AND
IT AGAIN QUICKLY REVERSED IT.
BUT IT WAS NEVER TRIED BEFORE.
WE USED USUALLY A LOWER DOSE FOR
THESE PATIENTS SO THAT THE
TOLERANCE IS USUALLY PRETTY WELL
AND THE MOST COMMON SIDE EFFECT
THAT WE SEE IS A RASH.
AND BECAUSE THE PATIENTS THAT
WE'RE TREATING WHERE THE DRUG
WORKS, IT DOESN'T WORK ON
EVERYBODY.
WE THINK IT REALLY WORKS ON GAIN
OF FUNCTION MUTATIONS WITHIN THE
PATHWAY THAT ARE RAMPING UP THE
PATHWAY SO IT MAKES SENSE.
ON PATIENTS, BECAUSE THEY HAVE
THAT ABNORMAL PART OF THE
PATHWAY, THE DRUG IS JUST
BASICALLY NORMALIZING THINGS
BACK DOWN, AND WE PUBLISHED ALSO
ABOUT A PATIENT WE TREATED AND
THERE WERE MULTIPLE ORGANS
EFFECTS BY TREATING WITH THE
DRUG AT A RELATIVELY LOW DOSE.
WE DON'T USE THE SAME DOSE AS
THEY USE FOR CHEMOTHERAPY TO
TREAT THIS.
NOW?
ADDITION TO THAT, BECAUSE I
MEAN, SO ALLEN TENENBAUM AND I
ARE ACTUALLY VERY, VERY CLOSE
FRIENDS.
OUTSIDE OF THE SCIENCE, BUT WE
HAVE BEEN TALKING TOGETHER WITH
A GROUP OF PRINCETON ABOUT USING
THESE DRUGS IN COMBINATIONS OF
OTHER DRUGS AND THERE'S A TRIAL
THAT'S GOING TO BE DONE FOR
THAT.
BUT THERE'S A LOT ABOUT THE
DIFFERENT PATHWAYS AND HOW THESE
DRUGS ARE FUNCTIONING THAT WE
SIMPLY DON'T UNDERSTAND.
WITH THOSE WHO HAVE ACTIVATION
OF THE PATHWAY AND YOU PUT THEM
ON TREE MENTIVE, IT DOES
WONDERS.
THEY TOLERATE IT WELL AND WEST
KEPT THEM ON IT FOR YEARS WITH
FEW SIDE EFFECTS.
>> THANK YOU FOR THAT.
>> NO PROBLEM.
>> THANK YOU, BOTH.
YEAH, YOU HAD SO MANY QUESTIONS
IN THE CHAT FOR BOTH MAX AND
YOAV SO I'M CALLING ON YOU NEXT
AND I'LL WORK OUR WAY THROUGH.
THANK YOU, GUYS.
>> THANK YOU.
THANK YOU Dr. DORI AND MAX.
IT'S SUCH A FANTASTIC AND
EXCITING TALK.
SO MY QUESTION IS ABOUT THE
LIVER CAP YOU LAR LYMPHATIC
SYSTEM WHICH IS NOT STUDIED BUT
IT'S VERY IMPORTANT,
PARTICULARLY IN HUMAN CAN SEE A
LOT OF LYMPHATIC VESSEL DEVELOP
IN THE CAPSULAR AREA.
MY QUESTION IS, LIVER CAP YOU
LAR LYMPHATIC VESSEL COMMUNICATE
WITH PORTAL LYMPHATIC VESSEL BUT
THE DRIVEN TO THE SAME LYMPH
NODE AS THE PORTAL LYMPH NODE
ARE THERE ANY COMMUNICATION
BETWEEN THE LUNG LYMPHATICS?
>> SO, DEFINITELY THE LIVER
LYMPHATICS CAP ZOO LAR AND
SOMETIMES EVEN LYMPHATIC
COMMUNICATE THROUGH WITH THE
(INAUDIBLE), THAT'S ATOMICAL TO
ME BUT I THINK IN THE PAPERS YOU
ARE ACTUALLY RIGHT IT SHOWS IT.
WE SEE IT IN CLINICAL, OF
COURSE, SUCH BRONCHITIS, PLURAL
INFLATION AND MAYBE SOME OTHER
DISEASES WE DIDN'T DISCOVER YET
BECAUSE UNFORTUNATELY WE HAVE
TOOLS RIGHT.
SO PEOPLE DO KNOW HOW TO REFER
TO US.
IN MY INSTITUTION WHEN PEOPLE
ASK WHAT PATIENT WE HAVE TO
REFER TO, THE ANSWER IS
SOMETHING LEAKING SOMETHING
SWOLLEN OR COMPLETELY LOST AND
70% OF THE TIME WE FIND
SOMETHING LYMPHATIC RELATED TO
THAT.
WE HAVE DEFINITELY THERE'S
PATHOLOGY MECHANISM OF CERTAIN
DISEASES BUT WE'LL DISCOVER
PROBLEM MORE AND MORE IN THE
FUTURE.
FOR SURE.
THIS IS SOMEONE ELSE'S QUESTION?
SO GENERALLY THE IS COMPLEX.
THERE'S MULTIPLE COMMUNICATIONS
FROM DIFFERENT EVERYWHERE THE
LIVER ATTACHED TO THE SURFACE OF
THE PER TEENIAL IT'S
COMMUNICATIONS AND THAT'S
SOMETIMES IT'S DIFFICULT TO
PREDICT.
YOU HAVE TO IMAGE ALL OF THOSE.
SOMETIMES IMAGING IS DIFFICULT
BECAUSE IMAGE ONE PART OF THE
LYMPHATIC SYSTEM AND DIDN'T SEE
THE OTHER ONE THAT DOESN'T FEEL
FROM THIS SO IT'S A COMPLEX
ISSUE OF COURSE.
AND GEOGRAPHY OF THE LIVER HELPS
SIGNIFICANT TO UNDERSTAND THAT.
>> SO THE LYMPHATIC VESSEL DRAIN
TO DIFFERENT LYMPH NODE COMPARED
TO?
>> YEAH, THEY COMMUNICATE
(INAUDIBLE).
>> SO DEFINITELY, YEAH.
IT WAS LYMPH NODES OR LYMPHATIC
STRUCTURES.
>> THEY'RE DIFFERENT.
OK.
>> IF I ADD ONE THING TO THAT, I
MEAN, IF YOU LOOK AT THAT
ARTICLE YOU PUBLISHED ABOUT THE
DIFFERENT CONNECTIONS, THE
DRAINING TO THE LYMPH NODES, CAP
SIL I AM FAD I CAN DRAIN UP BUT
DIFFERENT PARTS OF THE LIVER
DON'T CONNECT TO THE CAPSULE OR
LYMPHATICS THAT ARE DRAINING UP.
SO IF YOU ACCESS DIFFERENT
PORTIONS OF THE LIVER, YOU WILL
GET SOME CONNECTIONS THAT ARE
CONNECTING TO THE CAPSULE THAT
THEN GO UP AND IN CERTAIN
PORTIONS OF THE LIVER, DRAINING
IS GOING DOWN AND UNDER NORMAL
CONDITIONS, YOU WON'T SEE IT UP
INTO THE LUNG.
BUT HAVING LUNG LYMPHATICS FOR
EXAMPLE IN THE PAPER I TALKED
ABOUT, THE GONE OWE PHENOTYPE
YOU SEE MUTATION YOU DON'T SEE A
THORACIC DUCT BUT CAPSULE
LYMPHATICS PUNCTURING ACROSS THE
DIAPHRAGM GOING UP TO THE
BRONCHIAL LYMPHATICS AND THERE
ARE LYMPH NODES THERE BUT I'M
NOT SURE EXACTLY -- THE LYMPH
NODES ARE THERE BUT I'M NOT SURE
IF IT'S DRAINING TOWARDS THEM OR
IF THAT'S THE PATHWAY IT TAKES.
>> THANK YOU, VERY MUCH FOR
BOTH.
IT'S VERY INTERESTING.
>> THANK YOU BOTH.
AND SO, NILS, YOU ARE ON DECK
NECK AND CELINE WILL ASK A
QUESTION.
THIS IS A REALLY GOOD HIGH-LEVEL
QUESTION FROM THE AUDIENCE.
WHAT TOOLS OR VISUALIZATIONS
EXIST TO TRANSLATE DATA TO HELP
RESEARCHERS, PHYSICIANS AND
PATIENTS MAKE BETTER DECISIONS
TOGETHER.
I LIKE THE TOGETHER ASPECT.
>> THANK YOU FOR THE QUESTION.
AND I THINK THIS IS IN DEED AN
EXCELLENT QUESTION.
I WANT TO EMPHASIS THE TOGETHER
ASPECT OF THIS QUESTION.
IT'S QUITE DIFFERENT, I THINK,
FROM WHAT I SHOWED TODAY.
SO WHAT I SHOWED TODAY, THESE
VISUALIZATIONS ARE TARGETED TO
RESEARCHERS, RIGHT.
THIS IS DATA FAIRLY RAW DATA IN
A WAY ALTHOUGH IT'S VISUAL, AND
IT HELPS WITH UNDERSTANDING SOME
BASICS AT THE MOLECULAR LEVEL.
IF YOU ARE INTERESTED IN MAKING
DECISIONS TOGETHER, SORT OF A
SHARED DECISION-MAKING
VISUALIZATION, WHAT WE NEED TO
TAKE INTO ACCOUNT, THIS HAPPENS
TO BE ANOTHER AREA OF MY
RESEARCH IS WHAT IMPLICATIONS
WOULD THESE DECISIONS HAVE ON
THE PATIENTS, RIGHT.
SO YOU ARE INTERESTED IN
UNDERSTANDING POTENTIAL
OUTCOMES, RISKS ASSOCIATED WITH
CERTAIN STRATEGIES, TREATMENTS,
ET CETERA, BUT EVEN THOUGH IT'S
NOT A TRIVIAL PROBLEM TO SOLVE,
I THINK IT IS REALLY A VERY
IMPORTANT DIRECTION OF RESEARCH
TO UNDERTAKE BECAUSE IN FACT,
DATA VISUALIZATION CAN BE AN
EXCELLENT TOOL FOR COMMUNICATION
BETWEEN STAKEHOLDERS BUT
DIFFERENT LEVELS OF
UNDERSTANDING OFF THE PROBLEM
AND DIFFERENT PERSPECTIVES SO WE
HAVE DONE SOME WORK ON POTENTIAL
OUTCOMES OF SURGERIES, AND
DIFFERENT TYPES OF SURGERIES AND
HOW THIS WOULD ACT OF PATIENT
AND THEIR TRAJECTORY AND SO IT'S
A GREAT OPPORTUNITY TO GET
PEOPLE AT THE SAME TABLE SO
LEVEL THE PLAYING FIELD A LITTLE
BIT SO THAT PATIENTS CAN ASK THE
QUESTIONS ABOUT THEIR CONDITION
AND ABOUT POTENTIAL TREATMENTS
BASED ON THE DATA THAT'S BEEN
PRESENTED TO THEM.
>> THANK YOU SO MUCH, NILS.
AND IF THAT WAS A GREAT QUESTION
AND WE'LL ASK SALEN TO ASK A
QUESTION TO HELENE.
>> ALL THE TALKS WERE GREAT AND
THANK YOU FOR THIS GREAT
SESSION.
I WAS GOING TO ASK HELENE, IT
MIGHT BE, I GUESS IT APPLIES TO
ALL THE ORGAN SYSTEMS WE SAW BUT
IS THERE A POSSIBILITY THAT THE
INDIVIDUAL VARIANTS IN THE
ANATOMICAL PATHWAYS OF THE GLIM
MIGHT BE THE UNDERLYING REASON
WHY SOME INDIVIDUALS WITH THE
PLAQUES THE POSITIONS THEY DON'T
DEVELOP THE COGNITIVE
DYSFUNCTION AND SOME DO?
>> WHAT A GREAT QUESTION.
I SAW IT AND I SAID WHAT A GREAT
QUESTION.
THERE ARE DATA SHOWING WHEN YOU
REALLY BLOCK, THEY HAVE ANOTHER
TECHNIQUE THEY DO BASE DINE AND
THE SYSTEM IS FAILING.
THEY HAVE BEEN REPORTING
COGNITIVE CHANGES WITH THAT SO
YES, I MEAN, THERE MIGHT BE A
LINK BETWEEN COGNITIVE DECLINE
AND BEING ABLE TO DRAIN AND THAT
COULD BE ANATOMICAL VARIATIONS
AND CLEARLY, I MEAN, IT'S A
GREAT QUESTION.
THANK YOU.
>> GREAT.
THANK YOU SO MUCH.
I'LL LET BABAK, BECAUSE THE
CHAIR DUTIES ASK THE FINAL
QUESTION IF YOU CAN DO IT
QUICKLY AND WE'LL TAKE A BREAK
AND THE PANELISTS AND HOSTS CAN
ANSWER ANY REMAINING QUESTIONS
IN THE CHAT.
>> REALLY BEAUTIFUL
PRESENTATIONS.
HOW DO WE DISSEMINATE THESE
ABILITY TO DID THESE IMAGING?
THEY'RE NOT WIDELY AVAILABLE AND
GETTING LYMPH ANGIO GRAMS IS
VERY DIFFERENT AND THEY'RE HARD
TO INTERPRET.
HOW DO WE OVERCOME THAT PROBLEM?
>> YOU MEAN, HOW TO SPREAD THE
TECHNOLOGY OR TECHNIQUE OR HOW
TO --
>> WE CAN'T REALLY, IT'S VERY
VARIABLE GETTING ANGIO GRAMS AND
SOMETIMES UNINTERPRETABLE.
HOW DO WE DO THAT MORE IN MORE
RADIOLOGY PROGRAMS.
>> YOU HAVE TO FIND THE PILLS
BUT IT IS INTERESTING TO THAT
AND EVERY PLACE I WORK WITH,
SOMEONE WANTS TO DO THAT AND
IT'S DIFFICULT TO SET UP BECAUSE
OF COMMENT PLECOMPLEXITY OF MRIE
REALLY EASY SO THAT'S WHAT I
STARTED TO SEE DIFFERENT PARTS
OF THE WORLD WITH MRI ACCESS
LESS, THEY STARTED TO DO CT
GEOGRAPHY AND IT WOR AMAZINGLY .
THE ONLY THING IS THE RADIATION
AND YOU COULDN'T GET AT THIS
MOMENT THE DYNAMIC INFORMATION
BUT REALLY JUST GET WHERE WE DID
ALL THE TECHNIQUE WHERE WE CAN
ACTUALLY PERFORM IT BASED ON CT
AND THAT WILL BE A BIG PROGRESS
BUT CT IS THE WAY TO GO FOR THE
SMALL PROGRAMS AND THE PEOPLE
THAT DON'T HAVE THE (INAUDIBLE).
>> THAT'S GOOD ADVISE.
>> IADVICE.COME AND LEARN, WE SE
PROGRAMS AROUND THE WORLD SO YOU
KNOW, IT'S TRUE THAT NOT EVERY
PLACE ON THE PLANT IS GOING TO
HAVE THE CAPACITY TO DO THAT BUT
AGAIN, THERE'S IN ORDER TO
UNDERSTAND THE WHOLE THING YOU
NEED TO UNDERSTAND THE FLOW AND
YOU NEED TO UNDERSTAND THE
DYNAMICS.
YOU NEED TO UNDERSTAND THE
ANATOMY.
THERE'S NO SUBSTITUTE.
CT IS OK FOR CERTAIN THINGS BUT
AMR CONTRAST IS THE BEST.
IT FLOWS MOST DISTAL' AND IT
WORKS WHEN IT'S DILUTED SO IT
SHOWS YOU EVERYTHING THE BEST.
CALL US, COME OVER AND LEARN HOW
TO DO IT.
IT'S NOT THAT COMPLICATED.
>> SOUNDS GOOD.
>> THANK YOU.
THANK YOU SO MUCH.
THANK YOU, GUYS.
SO, WE WILL TAKE A BREAK AFTER
REALLY EXCITING SESSION AND THE
LAST OF THE SYMPOSIUM AND THEN
WE'LL BE BACK HERE IN 10 MINUTES
AT 3:00 TO CLOSE OUT WITH A
SPECIAL SESSION SO THANK YOU
ALL.
COME BACK --
>> WE'LL BE BACK AT 3:05.
WE EXTENDED TO GIVE YOU A CHANCE
FOR A FULL DISCUSSION.
>> THANK YOU SO MUCH.
SO 3:05.
SEE YOU IN A FEW MINUTES.
THANK YOU, ALL.
>>READY FOR THE LAST AND MOST
IMPORTANT SESSION.
PLEASE, TAKE IT AWAY.
>> GREAT.
THANK YOU.
THANK YOU FOR STAYING TO THE
END.
BABAK AND I PREPARED REMARKS
CLOSING OUT THE SESSION GRADES
ON THE GAPS AND OPPORTUNITIES
YOU PROVIDED.
OF THE LAST FEW DAYS HAVE
HIGHLIGHTED THE IMPORTANCE OF
THE LYMPHATIC SYSTEM AND HEALTH
AND DISEASE.
WE'VE BEEN IMPRESSED BY SCALE,
SPECIALIZATION, AND IMPORTANCE
FOR NORMAL PHYSIOLOGY AND
IMPLICATIONS AND A WIDE RANGE OF
DISEASES, DESPITE THE CHALLENGES
AHEAD, WE HAVE MANY REASONS TO
BE HOPEFUL FOR THE FUTURE OF
LYMPHATIC RESEARCH.
INVESTMENT IS THE NIH, THE
WORLD'S LARGEST FUNDER OF
BIOMEDICAL RESEARCH.
Dr. STEVEN JAMES THE DIRECTOR
OF DIVISION OF DIE JESS
ADVERTISE DISEASES AND DAVID GOV
FROM THE DIVISION OF SCIENCES
AND SHARED NIH'S VISION FOR
LYMPHATIC RESEARCH WITHIN NIDDK
AND NHLBI R RESPECTIVELY INCLUDG
THE LYMPHATIC RELATED RESEARCH
DISEASE RESEARCH CONDITION
DISEASE CATEGORIES.
Dr. RAILCAR DISCUSSED FUNDING
MECHANISMS TO EXCELERATE BENCH
TO BEDSIDE APPROACH.
AND INCLUDING THE CREATION OF
THE HUMAN BIO MOLECULAR ATLAS
PROGRAM, MEDICINE TASK WITH
MAPPING ALL CELLS AND TISSUES OF
THE HUMAN BODY WE'RE DELIGHTED
BY A NEW INITIATIVE AND FINALLY
SARENA THEY ESTABLISHED A
TRANS-NIH COORDINATING COMMITTEE
FROM MEMBERS OF 12 OF 27 NIH
INSTITUTES AND CENTERS FROM
REPRESENTATIVES FROM SEVERAL
PATIENT ADVOCACY GROUPS AS THE
AFRICAN PROVERB STATES, IF YOU
WANT TO RUN FAST RUN A GONE, IF
YOU WANT TO RUN FAR, RUN
TOGETHER.
WE ARE GRATEFUL FOR PATIENTS,
ADVOCATES, CLINICIANS
RESEARCHERS AND THE NIH FAMILY.
>> THANK YOU.
THIS WORKSHOP WAS DESIGNED TO
BRING TOGETHER BASIC
TRANSLATIONAL AND CLINICAL
EXPERTS TO PRESENT THE LATEST
ADVANCES IN THE FIELD AND ENGAGE
IN INTER DISCIPLINARY
DISCUSSIONS.
WE ASKED OUR SPEAKERS TO
IDENTIFY KNOWLEDGE GAPS AND
OPPORTUNITIES IN LYMPHATIC
RESEARCH.
OUR CONTRIBUTORS IDENTIFIED MANY
GAPS AND I'LL BROADLY SUMMARIZE
THESE.
EARLY DIAGNOSIS IS NUMBER ONE.
NUMBER WHO IS QUANTIFICATIONS OF
THE LYMPHATIC FUNCTION AND
EVALUATION OF LYMPHATIC AN AT
MAY AND NUMBER THREE IS
LYMPHATIC-SPECIFIC FARM CO
THERAPIES AND NUMBER FOUR IS
AVAILABLE ANIMAL MODELS AND I'LL
GO THROUGH SOME OF THESE IN
DETAIL.
ONE OF THE MOST FRUSTRATING
THINGS FOR PHYSICIAN AND
PATIENTS ARE NON-INVASIVE
DISEASE LEADING TO DELAYED
DIAGNOSIS.
WE DON'T HAVE ANY DRUGS THAT
IMPROVE LYMPHATIC FUNCTIONING
WITHOUT SIGNIFICANT OFF TARGET
EFFECTS.
ANIMAL MODELING INOF VARIOUS
DISEASES, KIDNEY DISEASE, LIVER
DISEASE AND OTHERS HAVE SHOWED
IMPROVING WITH VEGFC O OTHER
GROWTH FACTORS IS HELPFUL
HOWEVER THIS IS NOT CLINICALLY
TRANSLATABLE SINCE THESE
TREATMENTS CANNOT BE
ADMINISTERED LONG-TERM.
ANIMAL MODELS AND THERE'S AN
IMPORTANT NEED FOR LYMPHATIC
MUSCLE CELL SPECIFIC DRIVERS.
CROW DRIVERS.
THESE DRIVERS WOULD HELP US
UNDERSTAND WHY AND HOW LYMPHATIC
MUSCLE CELLS DEVELOP AND
REGENERATE.
IT'S IN MANY DISEASES SUCH AS
OBESITY AND THIS PROBLEM IS DUE
TO THE COMPLEXITY OF ACCURATELY
IMAGING LYMPHATIC VALUES IN VIVO
AS Dr. MICHAEL DAVIS NOTED,
VERY FEW STUD SEIZE HAVE BEEN
DONE ON HEALTHY HUMAN VESSELS TO
LOOK AT LYMPHATIC MUSCLE
FUNCTION AND MOST REALLY RELY ON
IN VITRO OR ANIMAL MODELS THAT
LACK GRAPH STATIONAL LOADS THAT
ARE PRESENT IN HUMAN LIMBS.
TECHNICAL DIFFICULTIES IN STUDY
THE HUMAN LYMPHATICS WITH MUSCLE
CELLS HAVE RESULTED IN ABUNDANCE
OF WORK IN LYMPHATIC AND CELLS
AND DIVERSE FUNCTION OF
LYMPHATIC MUSCLE CELLS.
A LOT OF THESE LINES, IT'S CLEAR
THAT DEVELOPING METHODS FOR
LYMPHATIC FUNCTION IS IMPORTANT
USING ADVANCED IMAGING, SODIUM
MRI AND OTHER TECHNIQUES IS
PROMISING AND I THINK
TRANSLATING THIS PRACTICE TO FOR
PATIENTS AND DISSEMINATING THIS
TECHNIQUES WIDELY IS IMPORTANT.
Dr. NICHOLS, IDENTIFIED GAPS
IN CONNECTING VARIOUS PATHOLOGIC
PROCESSES THAT HAVE BEEN
IDENTIFIED SUCH AS INFLAMMAT
INFLAMMATION -- THE NEED FOR MOE
LYMPHATIC CENTERS OF EXCELLENCE,
SPECIALIZED TRAINING FOR MEDICAL
STAFF AND TREATMENT OF IMAGING
OF LYMPHATIC DISORDERS, CREATIVE
APPROACHES SUCH AS STATE OF THE
ARTERY SEARCH AND CENTERS FOR
CHILDREN AND ADULT PATIENTS.
WE HAVE HEARD EXCITING REPORTS
ABOUT THE BASELINE DIFFERENCES
IN LYMPHATIC ANATOMY AND THE
EFFECT OF THE DIFFERENCES ON THE
RISK OF DEVELOPMENT.
FUTURE EXPERIMENTS TO HERM TO
YOU THEY MAY CONTRIBUTE TO LOWER
EXTREMITY.
THERE'S SCALE TRIALS ANALYZING
OUTCOMES WITH THE GOAL OF
DEFINING OPTIMAL SURGICAL CAL
ALGORITHM AND ANIZING THESE
OUTCOMES LONG-TERM.
THEY'RE NEEDED FOR INFLUENCE
COVERAGE AND HAVE TOX SIT TEE
FOR OUR PATIENTS AND THERE'S A
MAJOR NEED TO DETERMINE THE
PREVALENCE OF LYMPHATIC DISEASES
ALONG WITH INCREASED PHYSICIAN
EDUCATION AND PSYCHOSOCIAL
COUNSELING FOR PATIENTS WITH
LYMPHATIC DISORDERS AT THESE
DISEASES HAVE BEEN NEGLECTED.
>> THANK YOU SO MUCH, BABAK, FOR
OUTLINING THE MANY CLINICAL
CHALLENGES.
I'D LIKE TO DISCUSS THE
LIMITATIONS AND OBSTACLES WE
FACE AS BASIC RESEARCHERS.
A POPULAR THEME THROUGHOUT THE
WORKSHOP WAS THE HETEROGENEITY
OF LYMPHATIC AND CELLS
THROUGHOUT THE BODY.
Dr. OLIVER STONE DISCUSSED THE
DIVERSE ORIGINS AND THEIR
CONTRIBUTION TO ORGAN-SPECIFIC
PROGRAMS.
OUR SESSION 3 SPEAKERS FOCUSED
ON LYMPHATIC SYSTEM OF THE GI
TRACT AND METABOLICS DISORDER.
DR. SEUSS THE SYDNEY AND JOINT R
HEART AND BRAIN.
BEYOND SPECIALIZATION OF THE
LYMPHATIC SYSTEM, THERE WAS WORK
IDENTIFYING BOTH METABOLIC AND
IMMUNE LOGICAL DIVERSIFICATION
AND LYMPH NODES FROM THE PART OF
THE GUT AND DEMONSTRATED
DIFFERENCES IN THE LENGTH AND
STRUCTURE OF THE LYMPHATICS
ACROSS THE SMALL INTESTINE.
IN SUMMARY, THE LYMPHATIC SYSTEM
SPECIALIZED ACROSS ORGANS AND
WITHIN TISSUES.
BEYOND THE DIVERSIFICATION OF
THE LYMPHATIC SYSTEM WE LEARNED
ABOUT THE DISTINCT NICHE FROM
Dr. NATASHA, MICHAEL DAVIS,
RACHEL NICK AND DARIA.
OUR GREAT OF THE CHALLENGES ARE
DEVELOPING TOOLS AND
TECHNOLOGIES TO ACCURATELY
PROFILE LYMPHATIC PETTER OWE
-- AND DEVELOPING TRANSAGAIN IE
THESE POPULATIONS IN VIVO.
BACK TO YOU, BABAK.
>> ALTHOUGH WE IDENTIFIED MANY
GAPS AND DEFICIENCIES IN OUR
UNDERSTANDING OF THE LYMPHATIC
DISORDERS, THERE'S REASONS FOR
OPTIMISM.
INTEREST IN LYMPHATIC DISORDERS
IS AN ALL-TIME HIGH AND MORE
BRIGHT AND YOUNG INVESTIGATORS
AND THEY WILL DEDEASE THE BURDEN
OF THIS DISEASE FOR OUR
PATIENTS.
INCREASING OUR UNDERSTANDING OF
LYMPHATIC ANATOMY MAY DECREASE
THE RISK OF DEVELOPING
LYMPHATIC.
DEVELOPMENTS OF SURGICAL
TECHNIQUES AND COMBINATION OF
MEDICAL THERAPY TO IMPROVE WILL
HELP TREAT PATIENTS WITH
LYMPHATIC DISORDERS.
DECREASE COST OF TOOLS AND
SCREENING WILL HELP US IMPROVE
OUR LYMPHATIC DISEASES AND LEAD
TO BETTER TREATMENT AND EARLIER
DIAGNOSIS OF LYMPHATIC MALL
FORMATIONS, LIP EDEMA AND OTHER
DISORDERS AND THIS INCREASED
UNDERSTAND OF WILL UNDOUBTEDLY
LEAD TARGETED TREATMENTS
IDENTIFYING THE GAPS IN OUR
KNOWLEDGE IS THE FIRST STEP
TOWARDS THIS GOAL AND IT WILL
LEAD TO BREAK THROUGHS AND
INCREASE FUNDING FOR LYMPHATIC
RESEARCH WILL INCREASE OUR
KNOWLEDGE BASED AND EFFECTIVE
TEACHINGS.
>> EXCELLENT.
WE'RE GETTING CLOSE, GUYS, THANK
YOU.
SO, DESPITE THE CHALLENGES
IDENTIFIED BY WORKSHOP
PARTICIPANTS, AND PATIENTS, AND
ADVOCATES, WE ARE HOPEFUL.
THANK YOU FOR BEING ENGAGING AND
THOUGHTFUL PARTICIPANTS.
OVER THE LAST TWO CARRYING OUR A
NOVEMBEREL MODEL FOR FORM -- AND
THE FIRST FROM.
Dr. JOSHUA SCALING DICE SECTED
THE AK SIS FOR BUT THE OBJECT BN
AND LEARNED ABOUT SPACIAL AND
ADVANCE DATA ANALYSIS TO
RECONSTRUCT THE ACCESS
FURTHERMORE OTHERS PRESENTED HE
WILL GENERAELEGANT WORK USING I.
THE INCREDIBLE PROGRESS WAS
SHARED BY THE HUMAN CELL ATLAS
CONSORTIUM TO MAP ALL CELLS OF
THE HUMAN BODY.
THE CONSTRUCTION OF AN ATLAS OF
THE VASCULARTURE CELLS AT THE
LYMPHATIC SYSTEM IS A GREAT
NEED.
Dr. GEHLENBORG SHOWED TOOLS
HIS TEAM DEVELOPED TO STUDY
MULTI SKILLED DATA AND THE
WEALTH OF DATA BY HUBMAP TO
IDENTIFY GENE AND PROTEIN
BIOMARKERS OF ORGAN SPECIFIC
LYMPHATIC CELLS.
>> OUR HOPE IS WE MADE SOME
INTRODUCTIONS.
AND INCREASE AWARENESS OF
LYMPHATIC DISORDERS.
WE NEED BROAD CROSS DISCIPLINARY
COLLABORATION TO SOLVE MAJOR
PROBLEMS THAT WE FACE AS
RESOU -->> LAST LASTLY, WE WANTE
BY EMPHASIZING THE NEED OF OPEN
SHARING FOR DATA, PROTOCOLS,
TRANSGENIC ANIMALS AND RESEARCH
FINDINGS TO ADVANCE THE FIELD.
A COMMITMENT TO OPEN SCIENCE AND
KNOWLEDGE DISSEMINATION IS KEY
TO IMPROVING ACCESS AND
DEVELOPING TREATMENTS FOR
LYMPHATIC DISORDERS.
WE ARE EMPOWERED BY HEARING
PATIENTS' STORIES AND BY YOUR
PASSION, CLARITY OF PURPOSE, AND
COMMITMENT TO BETTER CARE FOR
ALL.
>> THANK YOU AGAIN FOR YOUR
INTEREST AND ENTHUSIASM.
RESEARCH IS A TEAM SPORT.
WE HOPE THIS EVENT WILL FORGE
COLLABORATIVE PARTNERSHIPS AMONG
ALL OF YOU HERE.
AND WE HOPE THAT YOU HAVE A
GREAT DAY AND THANK YOU FOR
JOINING US TODAY.
I'M GOING TO TURN IT OVER FOR
FINAL REMARKS.
>> THANK YOU.
IT'S MY PRIVILEGE TO CLOSE THE
WORKSHOP AND HAVE A THANKS FOR
GRATITUDE TO EVERYONE WHO
CONTRIBUTED IN EVERY STEP OF
THIS WORKSHOP AS THE NIH
ORGANIZING COMMITTEE AND WE
WOULD LIKE TO THANK TO ALL NIH
MEMBERS AND PATIENTS ADVOCACY
GROUPS GUESTS OFF THE TRANS NIH
LYMPHATIC COORDINATION FOR THEIR
VALUABLE INPUT AND SUPPORT.
WE WOULD LIKE TO EXTEND OUR
SINCERE APPRECIATION TO GRAND
RANDOLPH FOR SHAPING THIS
WORKSHOP AND WE CAN'T THANK
ENOUGH TO ANDREA AND BABAK FOR
THEIR IMPORTANT CONTRIBUTION,
THEIR VISION, PASSION AND THEIR
HARD WORK TO MAKE THIS WORKSHOP
HAPPEN.
THEY COMMITTED MANY HOURS OF
THEIR BUSY TIMES.
THANK YOU SO MUCH AND ALL THESE
EFFORTS COMBINED WITH THE MOST
INTERESTING TALKS AND ENGAGING
DISCUSSIONS OF OUR SPEAKERS AND
MODERATORS WE LEARNED A LOT IN
THESE TWO DAYS.
WE CAN'T THANK YOU ENOUGH TO OUR
SPEAKERS TO INITIATE A BETTER
UNDERSTANDING.
HOW THEIR LIVES ARE EFFECTED IN
MANY LEVELS AND THEY HIGHLIGHTED
THE NEEDS OF THE COMMUNITY TO
COMPLIMENT THE RESEARCH WITH THE
PATIENTS EXPERIENCES, IT'S VERY
VALUABLE.
THANK YOU ALL FOR THE CONSULTING
GROUP FOR THE SUPPORT AS AS WELL
AS THE NIH MEDIA CAST TEAM FOR
THIS VIRTUAL EVENT.
IT MAGICALLY HAPPENS.
THANK YOU SO MUCH FOR THAT.
AND ALSO, WE WOULD LIKE TO
EXTEND OUR SPECIAL THANKS TO
SERENA.
I'M REALLY THANKFUL FOR HER
MENTORSHIP ALSO AND SHE IS THE
ONE WHO SPEARHEADED THIS YET TO
BE CHARTED SEMINARS AND SHE
CONTINUES TO SHARE HER VISION TO
MOVE THE FIELD FORWARD.
THANK YOU.
AND WE HOPE THAT THIS WORKSHOP
REACHED ITS GOAL TO INFORM ALL
OF US ABOUT THE LATEST ADVANCES
IN LYMPHATIC RESEARCH AND
PROVIDED A PLATFORM FOR THE
THOUGHT PROVOKING DISCUSSIONS
AND LAST BUT NOT LEAST, WE WOULD
LIKE TO THANK YOU FOR LISTENING
AND JOINING IN THE DISCUSSIONS
OF THIS WORKSHOP AND WE HOPE WE
GAVE A GOOD OFF LINE FOR THE
OPPORTUNITIES IN LYMPHATIC
RESEARCH WHICH WE SHOULD WORK
ALL TOGETHER TO ADVANCE THIS
FIELD AND FINALLY, WE ARE ENDING
WITH A HOPEFUL NOTE ECHOING
ANDREA AND BABAK'S NOTE THAT
THERE'S ALREADY A GREAT
LYMPHATIC COMMUNITY AND WE WILL
WORK TO MAKE IT BETTER AND WE
ARE READY TO TAKE THE EFFORTS TO
IN THE NEXT LEVEL TO PROVIDE
HELP AND HOPE TO MAKE THE LIVES
OF THE PEOPLE WITH LYMPHATIC
DISEASES BETTER.
I HOPE YOU HAVE A GO GOOD VERY D
EVENING.
>> THANK YOU, EVERYONE.
>> THANK YOU.