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AUDIENCE HERE.
SO TODAY'S CPC CASE IS A
PHENOMENAL CASE HOW HERE AT THE
CLINICAL CENTER, THE IMPACTFUL
CLINICAL RESEARCH THAT HAS MAJOR
IMPLICATIONS IN THE HEALTH OF
PATIENTS AND PLUS ACCOMPANIED BY
IMPORTANT FUNDAMENTAL RESEARCH
ASSOCIATED WITH THIS SO THE
PRESENTERS FOR TODAY'S TALK ARE
JEREMY DAVIS, SURGICAL ON COIN
PROGRAM AT NCI, Dr. KO RMAN AT
IDK, Dr. KIM, A STAFF PATH
GIFT AND RESEARCH PHYSICIANS AND
GRACE-ANN FASAYE, COUNSELOR AT
THE GENETICS BRANCH AT THE
CENTERS FOR RESEARCH AT NCI.
WITH NO FURTHER ADIEU, WE WILL
BEGIN OUR TALK TODAY.
LET'S GET IT GOING.
>> OKAY, Dr. HELLER IS HERE SO
WE CAN START.
[LAUGHTER]
>> I AM GOING TO START OFF TODAY
WITH A DEFINITION.
THAT IS JUST TO GET EVERYBODY ON
THE SAME PAGE.
SO WE'RE GOING TO TALK TODAY
ABOUT GASTRIC CANCER BUT
SPECIFICALLY ADENOCARCINOMA
WHICH ACCOUNTS FOR 95 PERCENT OF
ALL GASTRIC CANCERS ON THE
LINING OF THE STOMACH.
WE WILL TALK ABOUT DIFFUSE TYPE
CANCERS, A POORLY COHESIVE
CANCER THAT HAS SIGNANT RING
CELLS WHICH ARE A PORTION OF
CELLS BUT NOT ONLY IN THE
STOMACH, SIGNET AND THEN CDH1
EDITING CODES WE SEE IN PROTEINS
AND WE WILL TALK A LOT ABOUT
CDH1 TODAY AND I KNOW WE'LL
START WITH THE CASE
PRESENTATION.
THIS IS AN 11-YEAR-OLD BOY WITH
A DIAGNOSIS OF ADHD AND AUTISM
SPECTRUM STORED.
HE HAD A GENETIC WORKUP FOR
THESE CONDITIONS AND IT LED TO
AN INCIDENTAL FINDING OF A
GERMLINE CDH1 PATHOGENIC VARIANT
AND GRACE-ANN WILL TALK ABOUT
THAT A LITTLE LATER WHEN SHE
TALKS ABOUT THE GENETICS.
RELEVANT HISTORY, HE WAS BORN
PREMATURELY, SPENT A MONTH ON A
VENT LATER, SPEECH DELAY, AUTISM
SPECTRUM DISORDER AND ADHD.
HE IS IN THE 6TH GRADE, LIVES AT
HOME WITH HIS PARENTS AND
SIBLINGS, GOES TO OT AND HAS
THERAPY BUT OTHERWISE LOOKS TO
BE A REGULAR 6TH GRADE KID.
SO HE NOW HAS THIS DIAGNOSIS OF
A GERMLINE PATHOGENIC VARIANT IN
THE CDH1 GENE.
THE PARENTS KNOW THIS BUT
WEREN'T PLANNING ON DOING
ANYTHING AT THE MOMENT BUT HE
DEVELOPED THIS NONSPECIFIC
ABDOMINAL PAIN, NOT EATING MUCH
AND THE MOM WAS CONCERNED AND
TOOK HIM TO THE PEDIATRICIAN AND
KNOWING HE HAD THIS GERMLINE
VARIANT, THEY PERFORMED AN
ENDOSCOPY IN JANUARY OF LAST
YEAR.
THEY TOOK MULTIPLE BIOPSIES BUT
ONE OF THEM CALLED GASTRIC
CARCINOMA, DIFFUSE TYPE AND
Dr. KIM WILL SHOW THE
PATHOLOGY LATER.
HE WAS IN ANOTHER STATE AND WAS
WORKED UP AT A CHILDREN'S
HOSPITAL AND AS YOU WOULD DO
WITH A GASTRIC CANCER, THEY GOT
A PET SCAN TO LOOK FOR EVIDENCE
OF METASTATIC DISEASE WHICH WAS
NEGATIVE.
IN GASTRIC CANCER, WE PUT A
CAMERA IN THE BELLY, LOOK AROUND
AND MAKE SURE THERE IS NO OCCULT
OF GASTRIC CANCER IN THE
PERINEUM AND THEN HE HAD A PORT
PLACED AND STARTED ON
CHEMOTHERAPY.
I WON'T GO INTO THE DETAILS BUT
THE STANDARD TREATMENT FOR
GASTRIC CANCER IN THE UNITED
STATES IS PREOPERATIVE
CHEMOTHERAPY, SURGERY AND
POSTOPERATIVE CHEMOTHERAPY.
AND THE POST STANCE IS 5-OP
CHEMOTHERAPY, USUALLY TWO
CYCLES, SURGERY AND THEN TWO
CYCLES -- MAYBE I AM WRONG, IT
IS FOUR CYCLES AND TWO CYCLES.
SHOULD HAVE GOTTEN THAT ONE
RIGHT, HUH?
HIS MOTHER WANTED A SECOND
OPINION AFTER THE FIRST ROUND OF
CHEMOTHERAPY AND I WILL PAUSE
THERE A BIT WHILE WE SET UP THE
REST OF THE DISCUSSION.
HE WAS DIAGNOSED WITH GASTRIC
CANCER AND TALKING ABOUT ADEN
OCARCINOMA.
WORLDWIDE IT IS VERY COMMON BUT
ONLY 35,000 CASES IN THE UNITED
STATES, ACCOUNTS FOR ONLY
1 PERCENT OF THE NEW CANCER
CASES IN THE U.S.
BUT FIVE-YEAR SURVIVAL IS POOR.
35PERCENT, FIVE-YEAR SURVIVAL SO
NOT A GOOD CANCER IF THERE EVER
WAS ONE.
AN INDIVIDUAL'S LIFETIME RISK OF
DEVELOPING GASTRIC CANCER IS
ABOUT .8 PERCENT AND THIS IS
SEAR DATA I PULLED DOWN
YESTERDAY.
YOU CAN SEE THE MEDIAN AGE IS
68.
VERY FEW PATIENTS UNDER THE AGE
OF 45 ARE DIAGNOSED WITH STOMACH
CANCER SO IT IS LIKE A LOT OF
CANCERS, A DISEASE OF AGING OR
OF THE AGED.
THE DIFFUSE TYPE GASTRIC CANCER,
THERE IS INTESTINAL TYPE AND
DIFFUSE TYPE AND THIS GOES BACK
TO THE 1960S BUT IS TRUE TODAY.
DIFFUSE TYPE DOESN'T FORM
MASSES, IT IS ILL FILL TRADED
AND YOU WILL SEE THE PICTURES IN
A LITTLE BIT.
BUT WHAT IS INTERESTING IS THIS
IS INCREASING IN YOUNGER AND
FEMALE GROUPS SO THAT RED LINE
IS THE CIRCLE THAT REPRESENTS
YOUNG WOMEN AND THAT NUMBER IS
GOING UPWARD.
SO WHY DO WE STUDY DIFFUSE
CANCER?
BECAUSE IT IS DIAGNOSED LATE IN
THE UNITED STATES AND MOST
PEOPLE ARE DIAGNOSED -- SORRY,
THIS IS SURVIVAL -- WHEN CANCER
IS DIAGNOSED LATE.
SO IF WE DIAGNOSE IT EARLY,
SURVIVAL IS ABOUT 75 PERCENT.
WE DIAGNOSE IT WITH REGIONAL OR
DISTANT SPREAD, SURVIVAL DROPS
PRECIPITOUSLY.
THERE ARE NO STRATEGIES THERE,
NO PRECURSIVE LESIONS, AND
THERAPIES ARE LARGELY
INEFFECTIVE.
AND WHAT IS TRUE TODAY IS
1-3 PERCENT OF GASTRIC CANCERS
ARE CONSIDERED INHERITABLE.
THESE NUMBERS AREN'T PERFECT BUT
WE THINK THEY ARE ABOUT RIGHT.
Dr. KIM IS GOING TO TALK ABOUT
PATHOLOGY BUT I WANT TO REMIND
EVERYONE FROM WHAT THEY HAVE
SEEN IN THE PAST, THIS IS THE
STOMACH, THE LUMEN IS ON THE TOP
SIDE.
WHEN WE TALK ABOUT MUCOSA, WE'RE
TALKING ABOUT THE HE WILL TEAL
Y'ALL LAYER AND LAMINA PROPRIA.
ANY CANCER IN THIS STAGE IS 21A,
WHAT WE WILL TALK ABOUT TODAY,
THEN WE HAVE THE MUCOSA AND
SUBMUCOSA.
ANY CANCERS IN THIS AREA ARE
T1B.
THEN YOU HAVE THE THICKER LAYER,
THE OUTSIDE OF THE STOMACH SO AS
YOU PROGRESS THROUGH THE WALLS
OR LAYERS OF THE STOMACH,
CANCERS BECOME HIGHER IN THE
TUMOR STAGE.
AND THEN LASTLY, CDH1 APPROACH,
THIS IS EPITHELIAL AND A CALCIUM
DEPENDENT PROTEIN AND THAT IS
HOW IT GOT ITS NAMES.
IT DEMONSTRATES WITH CELL CAN I
GOALING AND THE LAYER IN BLUE
CONNECTS TO THE ALPHABETA INSIDE
THE CELL AND THEN THE
CYTOSKELETON.
SO THE LOSS HERE IS KNOWN TO
DISRUPT ARCHITECTURE, SELF
POLARITY AND ADHESION.
AND WHAT WE WILL TALK ABOUT
TODAY IS LOSS OF FUNCTION
MUTATIONS THAT ARE CONSIDERED
PATHOGENIC MEANING THEY WILL
LEAD TO DISEASE.
SO THE DIFFUSE TYPE OF CANCER WE
WILL TALK ABOUT IS AN AUTOD
OMINANT SET OF CANCERS, WE WILL
FOCUS ON GAS STRICK CANCER TODAY
AND GERMLINE CDH1, LOSS OF
FUNCTION VARIANTS ARE THE MOST
COMMON CAUSE.
OTHER VAR AGAINST ASSOCIATED
CONTAIN PT1, NOT TALKING ABOUT
THAT.
ONLY ONE IN 10,000 BIRTHS BUT
THE TAKEAWAY IS IF YOU HAVE A
PATHOGENIC GERMLINE OF CDH1, THE
REMOVAL OF THE ENTIRE STOMACH TO
PREVENT STOMACH CANCER IS
RECOMMENDED AT THE AGE OF 20 TO
30 YEARS AND IF FOR SOME REASON
THE PATIENT DECLINES SURGERY OR
IS UNFIT FOR SURGERY, THEN
SURVEILLANCE WITH UPPER
ENDOSCOPY IS RECOMMENDED AND
THEN WOMEN WILL LIKELY DEVELOP
LOBULAR BREAST CANCER.
SO THOSE ARE THE TREATMENTS FOR
THOSE WITH CDH1 GERMLINE.
SO Dr. KORMAN WILL TALK ABOUT
THE PATHOGENIC SCREENING AND
THEN Dr. KIM AND GRACE-ANN
WILL TALK ABOUT THE REST.
>> THANK YOU SO MUCH FOR
ALLOWING ME TO TALK ABOUT THIS
VERY DIFFICULT SYNDROME.
I WILL TALK ABOUT THE CHALLENGES
OF ENDOSCOPIC SCREENING AND
SURVEILLANCE.
FIRST WE WILL BEGIN WITH AN
ANATOMY LESSON.
THE STOMACH IS A BAG UNDER THE
ESOPHAGUS FROM AND LEADING TO
THE FINGER THEY ARE AND
DUODENUM.
IT IS FUNDED BY THE PYLORIA, THE
CARDIA, THE OPENINGS, THE
GREATER CURVATURE AND LESSER
CURVATURE AND THEN AN ANT TEAR
WALL AND POSTERIOR WALL.
THE IMAGING TECHNOLOGY WE USE IS
AN UPPER [ ENDOSCOPE, FORWARD
VIEWING, HAS THE VIEW OF 200MM,
THE DIAMETER IS ABOUT 9.2MM.
IT HAS A LIGHT SOURCE, A LENS
WHICH PRODUCES A HIGH DEFINITION
IMAGE.
IT HAS A CHANNEL THROUGH WHICH
WE CAN PUT DEVICES AND IT HAS A
WORKING LENGTH OF ABOUT 10000MM.
THESE PROCEDURES ARE DONE UNDER
ANESTHESIA IN THE UNITED STATES.
FOR GASTRIC CANCER SCREENING
WHICH WAS DONE IN JAPAN AND
ASSOCIATED WITH H.PYLORI, THAT
WAS DONE WITH JUST THERAPY.
THE XENON LIGHT SOURCE PRODUCES
A WHITE LIGHT BUT YOU CAN -- WE
CAN VARY THIS LIGHT BY PUTTING A
FILTER IN WHICH PRODUCES A
DIFFERENT WAVE LENGTH SPECTRUM
CALLED NARROW BAND IMAGING OR
NBI.
THE CHALLENGE THAT WE HAVE IS
BECAUSE OF THE PECULIAR BIOLOGY
OF GASTRIC CANCER DUE TO CDH1.
ON THE LEFT YOU CAN SEE A
CARTOON OF THE AREAS WHERE THE
SIGNET RING CELLS DEVELOP AND
ESSENTIALLY THEY DEVELOP UNDER
THE SURFACE.
SO THE SURFACE MUCOSA APPEARS
SOMEWHAT NORMAL EVEN THOUGH
UNDERNEATH THE SURFACE, ALL
THESE SIGNET RING CELLS ARE
PRESENT AND YOU CAN SEE THIS IS
WHAT IT LOOKS LIKE AND THE PALE
AREAS HERE.
THE REASON I RAISE THE ISSUE OF
PALE AREAS IS THAT THEY ARE
IDENTIFIED DURING VISUAL
INSPECTION IN ENDOSCOPY AND
SEVERAL DOCTORS DATING BACK TO
2005 HAVE SUGGESTED THESE PALE
AREAS HAVE A HIGH PROBABILITY OF
HAVING GASTRIC CANCER.
SO USING HIGH DEFINITION WHITE
LIGHT ON THE LEFT, NARROW BAND
IMAGING ON THE RIGHT, THE IDEA
IS TO IDENTIFY THESE PALE AREAS
AS A METHOD FOR DETECTING EARLY
GASTRIC CANCER.
NOW, WE HAVE A SAMPLING
PROTOCOL.
THIS IS THE CAMBRIDGE PROTOCOL
DEVELOPED IN CAMBRIDGE AND IT
INVOLVES OBTAINING A TOTAL OF 30
BIOPSIES AND THIS IS THE
DISTRIBUTION.
THESE ARE MAPPED SO THAT THEY
ARE FROM THE CARDIA, THE BODY,
THE TRANSITIONAL ZONE WHICH IS
BETWEEN THE BODY AND THE ANTRUM
AND THEN THE ANTRUN AND
PRE-PYLORUS REGION.
THIS IS THE FIRST CASE, AN
11-YEAR-OLD WHO HAD AN ENDOSCOPY
HERE.
THIS IS THE ANTRUM AND YOU WILL
NOTICE THERE ARE NO
ABNORMALITIES ON THE SURFACE.
THIS IS THE BODY OF THE STOMACH.
THIS IS THE CARDIA AND FUNDUS
AND IF YOU LOOK THERE, THERE ARE
SOME SUBTLE CHANGES BUT THERE
AREN'T REALLY SIGNIFICANT
MUCOSAL ABNORMALITIES.
PLAY A LITTLE MORE OF THIS.
YOU CAN SEE THE HEARTBEATING
AGAINST IT.
THIS IS NARROW BAND IMAGING
WHICH EMPHASIZES MUCOSAL DETAIL.
THIS IS WHAT THE BIOPSY LOOKS
LIKE, THESE ARE RANDOM BIOPSIES
DONE IN THE ANTRUM AND THE BODY
OF THE STOMACH SO THIS PATIENT
HAD A TOTAL OF 30BIOPSIES AND
Dr. KIM WILL ADDRESS THE
RESULTS.
GO TO THE NEXT ONE.
WE DEVELOPED UNDER Dr. THEO
HELLER A DIFFERENT SAMPLING
PROTOCOL WHICH WE CALLED THE
BETHESDA PROTOCOL.
THIS IS 88 BIOPSIES.
THIS PROCEDURE TAKES 30 TO 45
MINUTES AND A NORMAL UPPER
ENDOSCOPY WOULD TAKE 10 TO 15
MINUTES SPECIAL THESE ARE HIGHLY
LOCALIZED.
SO YOU CAN SEE THE 88 BIOPSIES,
THE FUNDUS, AND SO WE HAVE A
FAIRLY ACCURATE MAP OF THE
DISTRIBUTION OF THESE
ABNORMALITIES.
THIS IS THE SECOND CASE WHICH
YOU WILL HEAR ABOUT OF A
34-YEAR-OLD FEMALE WHO WAS UNDER
SURVEILLANCE AND SHE HAD BOTH
TARGETED BIOPSIES AND BY
TARGETED, AN ABNORMALITY THAT WE
SEE AND THEN RANDOM BIOPSIES AND
BOTH TARGETED AND RANDOM WERE
POSITIVE AND YOU CAN SEE HERE
PALE AREAS BUT THERE ARE A LOT
OF PALE AREAS.
THIS IS THE ANTRUM, MULTIPLE
PALE AREAS, THIS IS THE BODY,
YOU CAN SEE SOME NODULARITY,
MORE PALE AREAS, THIS IS NARROW
BAND IMAGING AND PARTICULARLY
WE'RE DRAWN TO THIS AREA, MORE
PALE AREAS AND WE BIOPSY THIS
AREA.
YOU CAN BE SYMPATHETIC TO THE
PATHO LOGIST WHO HAD TO LOOK AT
88 SPECIMENS.
THESE ARE THE RESULTS PUBLISHED
FROM THIS INSTITUTION BY THE
GROUP ON THE 270 PATIENTS WHO
HAVE BEEN SCREENED SINCE 2017 TO
12/21 IN LANCET ONCOLOGY.
YOU CAN SEE ABOUT 90 PERCENT OF
THE CASES WERE BETHESDA.
THERE WERE 467 PROCEDURES, ABOUT
9 PERCENT WERE CAMBRIDGE.
THE DETECTION RATE IS
34 PERCENT, THAT IS 157 AND 157
OF 467 RANDOM BIOPSIES WERE
POSITIVE.
TARGETED ALONE, LESS THAN
1 PERCENT.
SO WE WERE NOT VERY GOOD AT
IDENTIFYING AN ABNORMALITY THAT
HAD CANCER IN IT AND THAT
NUMBER, IF YOU HAD BOTH TARGETED
AND RANDOM POSITIVES, THAT WAS
ALSO VERY SKEWED.
SO WE CAN DETECT ABOUT
34 PERCENT.
YES, SO I WILL CLARIFY THAT
THESE WERE SIGNET RING CELL
POSITIVE BIOPSIES AND AGAIN,
Dr. KIM WILL SHOW YOU WHAT
THAT LOOKS LIKE, BUT THESE
BIOPSIES ARE INTENDED TO DETECT
THE SUBMUCOSAL LEAGUES LESION OR
THOSE THAT ARE MORE INVASIVE.
YOU ALSO CAN SEE THESE
SURVEILLANCE NUMBERS THAT ARE
DECREASING OVER TIME AND THE
SIGNET CELLS THAT WERE POSITIVE
WERE 270 SO AGAIN WE WOULD
IDENTIFY 35 TO 40 PERCENT AND IN
TWO PATIENTS, THAT NUMBER IS
PROBABLY NOT VERY COULD IT.
ACCURATE.
THIS IS NOW UPDATED AND THIS
WORK IS CURRENTLY UNPUBLISHED,
REEF RANDOM BIOPSIES OF SIGNET
RING CELLS IN 28 PORTION OF THE
CASES.
WE ARE UP NOW TO 744 BIOPSIES.
IN TARGETING WHERE WE THOUGHT
THERE WAS AN ABNORMALITY, ONLY
12 OF 744.
IF THEY WERE RANDOM AND
TARGETED, MEANING BOTH WERE
POSITIVE, THAT WAS ABOUT
3.6 PERCENT AND WE FOCUSED
PARTICULARLY ON THE BIOPSYING OF
PALE AREAS AND WHAT THE YIELD
WAS AND IT WAS ACTUALLY NOT VERY
GOOD.
SO OF THE 149 PALE AREAS WE
IDENTIFIED, ONLY 21 WERE
ACTUALLY POSITIVE.
NOW, HERE AGAIN, WE CONTINUE
WITH SURVEILLANCE AND NOW WE'RE
UP TO A MEDIAN OF ABOUT 46
MONTHS OF PATIENTS WHO ARE BEING
MONITORED AND YOU CAN SEE THAT
THE DETECTION RATE FOR SIGNET
RING CELLS WITH PATIENTS AT RISK
DECLINING, IT REMAINS AT
APPROXIMATELY 35 PERCENT.
SO WHAT'S THE ROLE OF THE
ENDOSCOPY IN GASTRIC CANCER
DETECTION AND SURVEILLANCE?
SO ENDOSCOPY MAY BE THE
ALTERNATIVE TO REDUCING
GASITRECTOMY AND TODAY IN THIS
POPULATION, NO ADVANCED GASTRIC
CANCERS WERE IDENTIFIED BUT THE
RISK REMAINS UNKNOWN.
THE ENDOSCOPIC SURVEILLANCE IS
UNKNOWN, HAS NOT BEEN DEFINED,
THE APPEARANCES OF
ADVANCEDLESIONS ARE POORLY
DEFINED.
THE OPTIMAL EXAMINATION METHODS
FOR ENDOSCOPIC EXAMINATION ARE
NOT STANDARDIZED, WE HAVE RANDOM
BIOPSIES VERSUS THE TARGETING,
END THEY ARE OBSERVER VARIATION
AND ENDOSCOPIC TECHNOLOGY OR
MAGNIFICATION AND CONFOCAL
IMAGING AS WELL.
SO WITH THAT I WOULD LIKE TO
TURN IT OVER TO THE DOCTOR WHO
TREATED THESE CASES.
THANK YOU.
>> THANK YOU, Dr. KORMAN FOR
THE INTRODUCTION.
HI, MY NAME IS SUN A KIM FROM
PATHOLOGY AND TODAY I WOULD LIKE
TO PRESENT THE PATHOLOGY OF THE
SIGNET GASTRIC CANCER MASS ON
THIS BOY AND ALSO ANOTHER CASE,
A 34-YEAR-OLD FEMALE WHO HAD A
GASTRECTOMY AND I CAN SHOW THAT
ALSO.
ALL RIGHT, SO WE THINK THE
GASTRIC BY CROPS SEE, WE HAVE
THE SIG NET RING CELL IN THIS
AREA, WE CAN SEE THIS IN THE
LINING OF THE PROPIA FLOATING
AWAY TOWARDS THE EPITHELIUM.
AND THE CELLS ARE REPLACING AND
DECREASING THE NUCLEI OF THE
CELLS GIVING THE APPEARANCE OF
SIGNET RINGS.
AND THIS IS THE FIRST BIOPSY IN
2023, THE SIZE 1MM AND THE
STAINING IS A LITTLE DIFFERENT,
THE COLOR IS A LITTLE DIFFERENT
BECAUSE IT WAS DONE BY OUTSIDE
HOSPITAL BUT WE HAVE SPECIFIC
SIGNET RING CELLS IN THE PROPRIA
WITH CYTOPLASMA AND AS YOU LOOK
IN THIS WAY, THE CELLS ARE A
LITTLE HIGHER THE CELLS LOOK
DIFFERENT.
AND THE CELLS IN THIS BORDER HAS
MOVED CYTOPLASMA SO THE SIZE IS
SMALLER AND LESS GAS USING THE
EPITHELIAL.
AND INTERESTING THAT THE SIGNET
RING CELLS INVADING DEEP IN
THE --
[INDISCERNIBLE]
SO YOU HAVE THE RING CELL
FEATURE WITH PPMI BUT A
DIFFERENT TYPE OF THE SIGNET
RING.
SO WE HAVE THE CANCER CELLS
HERE.
THE ECADHERIN CAME FROM THE
EPITHELIUM SO THE PICTURE ON THE
RIGHT SIDE, THE CYTOKERATIN FOR
THE CMH1 GENE AND THE MEMBRANE,
YOU CAN SEE THIS BROWN STAINING
IN THE EXTERIOR MEMBRANE BUT IN
THE SIGNET RING, WE SEE LIGHT
BROWN STAINING IN THE CYTOPLASM,
NOT IN THE MEMBRANE SO IT LOSES
THE MEMBRANE EXPRESSION.
THE MOLECULE, MOSTLY COHESIVE
AND SINGULARLY ADHESIVE INSTEAD
OF MAKING ANY OTHER STRUCTURES.
SO THIS IS THE BIOPSY, THE BODY
BIOPSY, VERY SMALL FOCUS,
BIOPSIES OF FUNDAMENTAL CANCER
FROM THE ANTRUM AND THIS IS THE
ACTIVE SHIFT STAIN THAT
HIGHLIGHTS THE SIGNET RING CELL
AS WELL AS THE NEO PLASTIC
EPITHELIUM AND BECAUSE THESE ARE
VERY PATIENT DEPENDING ON THE
PATIENT, WE USE THESE STAINS TO
MORE EASILY SPOT THE CANCER
FIRST TIME.
IN THIS PICTURE, THERE ARE
BACKGROUND SIGNET CELL IN THE
BACKGROUND OF THE PROPIA BUT IF
YOU LOOK HERE, WE HAVE THE CELLS
IN THE GLAND LAR STRUCTURE AND
THEY HAVE THE STRUCTURE WITH YOU
THEY ARE RETAINED WITHIN THE
BLAND SO THIS IS WHAT WE CALL
SIGNET CELL CARCINOMA INSIDE.
SO I WOULD LIKE TO PRESENT THIS
CASE OF THE 34-YEAR-OLD FEMALE
WHO CAME TO US AS PATIENT
BECAUSE GASTRIC ISSUES WERE VERY
TYPICAL TO THE SIGNET CELL
CARCINOMA.
SO MULTIPLE BIOPSIES FROM
DIFFERENT AREAS SHOWS SIGNET
CELL CARCINOMA.
THE SIZES WERE SMALLER AND
TYPICALLY WE HAVE THIS SIGNET
CELL INFILTRATION IN THE MUCOSA
AND YOU CAN SEE THE INFILTRATION
IS MORE SMALLER COMPARED T THE
CELLS IN WHICH WE HAD VOLUME.
THIS SHOWS SIGNET CELLS FROM
MULTIPLE AREAS.
THIS IS FROM HER GASTRIC
SPECIMEN, THE TOP PART, AND THEN
THE BOTTOM PART WITH CARCINOMA.
AND THE EPITHELIUM IS LARGE R
AND THERE ARE TWO AREAS SO UPPER
LAYER WE SEE THESE CELLS.
THE LOWER LAYER WITH MORE --
[INDISCERNIBLE]
CELLS.
AND THIS HIGHLIGHT THE AREAS,
TYPICALLY DISTRIBUTED ALONG THE
MUSIC KOES IS A AND ALONG THE
EPITHELIUM SURFACE.
THEY DON'T MAKE MASS AND SO THIS
EXPLAINS WHY THE SIGNET CELL
SHOWS NO ABNORMAL APPEARANCE IN
THE ENDOSCOPY.
THERE ARE 94, LARGEST 16M BUT
THE SMALLER SIZE LESS THAN 1M
OVER THE STOMACH.
EVEN THESE LARGER NUMBERS, IN
THIS CASE SO THIS IS THE
PATHOLOGY AND NOW I DIRECT YOU
TO GRACE-ANN FASAYE.
>> THANK YOU, DOCTOR KIM AND
GOOD AFTERNOON, EVERYONE.
SO I AM GOING TO BE FOCUSING ON
THE CASE OF THE 11-YEAR-OLD BOY.
AND USING THAT TO HIGHLIGHT
TESTING, INDICATIONS FOR CDH1
AND DISCUSSING A PEN
TRANSETRANCE STUDY OUR TEAM IS
WORKING ON, SO PENETRANCE BEING
THE RISK OF DEVELOPING CANCER
BASED ON THE CDHM1 PATHOGEN.
SO AS YOU KNOW, THE 11-YEAR-OLD
HAD ADHD AND AUTISM SPECTRUM
DISORDER.
SO THE GENETIC WORKUP, THAT IS
WHAT REALLY LED TO THE
INCIDENTAL FINDING OF THE
PATHOGENIC VARIANT AND I WILL
DELL DELVE INTO THAT A LITTLE
MORE.
SPECIFICALLY WHEN IT COMES TO
TESTING FOR CDH1 IT CAN BE BASED
ON FAMILY FACTORS OR OTHER
FACTORS AND WHEN IT COMES TO
FAMILY CRITERIA, WE FOCUS ON THE
GASTRIC CANCER FOCUS AND USUALLY
IT IS A CASE OF LOBULAR BREAST
CANCER AND ALSO IF THERE IS A
BLOOD RELATIVE KNOWN WITH A CDH
VARIANT.
THE CANCER RISK IS NOT
CONSIDERED HE WILL VANITY IN
CHILDREN WITH CDH1.
IT IS CONSIDERED ADULT ONSET
CONDITION AND THERE IS NO
MEDICAL MANAGEMENT IN CHILDREN.
AND TESTING SHOULD WAIT TILL THE
AGE OF CONSENT WHICH IS USUALLY
18 BUT CAN BE EARLIER IF THERE
ARE ONSET CANCERS IN THE FAMILY.
SO THE QUESTION COMES AGAIN, HOW
DOES THE CDH1 GET PICKED UP.
SO THIS IS THE WORKUP AND THOSE
OF YOU FAMILIAR WITH FAMILY
TREES, THE CIRCLES REPRESENT
MALES, THE SQUARES THE FEMALES
AND THE ARROW POINTS TO THE
FAMILY.
YOU CAN SEE THERE IS HIGH
CHOLESTEROL, MOM HAS A CLEFT
PALATE AS WELL AS A MATERNAL
COUSIN BUT NO KNOWN FAMILY
HISTORY OF ANY CANCERS IN THE
FAMILY.
AS FAR AS INDIVIDUAL CRITERIA,
AGAIN, IT FOCUSES -- BECAUSE
FAMILIES CAN BE SMALL, SOME
PEOPLE DON'T KNOW THEIR FAMILY
HISTORY, SO CRITERIA HAS EVOLVED
OVER THE YEARS TO FOCUS ON THE
PATIENT IN FRONT OF AND YOU
FEIGN TO -- AGAIN TO LOOK AT
CDH1, IT CAN BE ANYONE WITH
CANCER AT ANY AGE, CLEFT PALATE,
MAORI ETHNICITY.
SO THIS WAS LOOKED AT WITH A
HIKE CROW ARRAY TO LOOK FOR
DELETIONS AND DUPLICATIONS IN
CHROMOSOMES WHICH CAN BE
INDICATION OF DEVELOPMENT
DISORDERS.
THIS IS SUPPORTED BY THE COLLEGE
OF PEDIATRICS AND GENOMICS, THEY
REPRESENT THIS FOR AUTISM AND
DEVELOPMENTAL DELAY.
SO WHEN THIS TEST IS DONE, IN
SOME CASES IT CAN PICK UP SOME
INCIDENTAL FINDINGS BUT NO
REASON TO SUSPECT CDH1 FOR
CANCER.
SO THERE IS ANOTHER CASE IN THE
LITERATURE WITH SIMILAR GENETIC
FINDING AS THIS CASE SO THAT IS
WHAT THESE IMAGES WERE TAKEN
FROM.
SO ON THE LEFT THERE IS
CHROMOSOME 16 WHERE CDH1 IS
LOCATED AND THE BLUE BAR ON THE
CHROMOSOME REPRESENTS A MICRODEL
LEAGUES THAT WAS IDENTIFIED ON
THE LONG ARM OF CHROMOSOME 16, A
245KB DELETION AND THIS IS THE
TWO EXONS FROM THE CDH1 GENE AND
THEN THE CHROMOSOME 15 WHERE THE
WHITE ARROW IS POINTING.
SO BECAUSE THIS MIKE CREE
>> Mike: CROW DEL LEAGUES WAS
FOUND AND WE KNOW THERE IS ONE
CDH1 GENE IN THE LOCATION, WE
RECOMMENDED TESTING FOR
RELATIVES AND FAMILY AT RISK AND
THE TESTING STARTED WITH THE
PATIENT'S MOTHER BECAUSE SHE HAD
CLEFT LIP AND PALATE SO SHE
SEEMED MORE LIKELY THAN THE
FATHER AND SHE WAS THE ONE THAT
TESTED POSITIVE.
THE OLDER SISTER WAS TESTED, SHE
WAS NEGATIVE.
EVERYONE ELSE WAS POSITIVE
INCLUDING MATERNAL UNCLE, AUNT,
ALL OF THEIR CHILDREN AND
MATERNAL GRANDMOTHER.
ONE OF THE MATERNAL COUSINS WAS
FOUND TO HAVE STAGE 1 GAS STRICK
CANCER AND OPTED FOR A
GASTRECTOMY AND A REPORT THERE
WHAT THE TEST LOOKED LIKE FROM
ONE OF THE RELATIVES.
SO THAT FAMILY HISTORY WAS
BEFORE THERE WAS ANY WORKUP AND
WITH NO CANCER HISTORY, WOULD
HAVE AN AN ANOMALY OF CDH120
YEARS AGO BECAUSE THE RISKS
PUBLISHED IN THE LITERATURE WERE
AS HIGH AS 83 PERCENT FOR WOMEN
AND 70 PERCENT FOR MEN.
AND YOU SEE IN THOSE STUDIES IN
2001 AND 2001 COMPARED WITH THE
SEAR POPULATION IS SIGNIFICANTLY
ELEVATED.
THE EARLIER STUDIES WERE SMALL
SAMPLE SIZES, FOUR IN ONE
FAMILY, IN ANOTHER 11 AND
DIFFUSE GASTRIC CANCER.
THE 2015 IS STILL THE MOST
CORRELATED STUDY, THEY FOUND 75
BUT STILL THREE OR MORE PATIENTS
WITH GASTRIC CANCER IN THAT
FAMILY.
THAT SHOWED A 70 PERCENT RISK
AND THEN 56 PERCENT RISK FOR
GASTRIC CANCER IN WOMEN.
THE RISK FOR BREAST CANCER IN
THESE PENETRANCE STUDIES HAVE
BEEN PRETTY CONSISTENT FOR
LOBULAR BREAST CANCER.
WHEN IT COMES TO IMPLICATIONS
FOR GENETIC TESTING, MANY WOMEN
UNDERGO TESTING BECAUSE OF
BREAST CANCER, DIAGNOSIS OR
CLINICAL HISTORY.
SO THE LARGE NUMBER OF LAPS THAT
PERFORM THE TESTING, OFTEN THEY
ARE DOING IT FOR THAT PARTICULAR
INDICATION.
SO TWO LAPS THAT OFFER CANCER
GENETIC TESTING, SPECIFICALLY
GENE PANEL TESTING WHERE THEY
LOOK AT SEVERAL GENES, CDH1 AND
THE MOST COMMON BREAST CANCER
GENE, TWO OF THOSE LABS
PUBLISHED THEIR CDH1, THERE WAS
A BIOPSY BECAUSE THESE PEOPLE
HAD CANCER OR FAMILY HISTORY BUT
NOT THE STRONG GASTRIC FAMILY
HISTORY AND THOSE STUDIES FOUND
A MUCH LOWER LIST OF GASTRIC
CANCER, 24 TO 42 PERCENT
LIFETIME RISK.
AND SO HERE AT NCI, OUR TEAM, WE
ARE LEADING A PENETRANT STUDY
BECAUSE WE HAVE A LARGE NUMBER
OF FAMILIES, WE WANTED TO DO A
MULTISITE STUDY AND SO WE HAD
PARTNERED WITH THE CANCER AND
GENETICS PROGRAM AS MASS
GENERAL, STANFORD UNIVERSITY AND
ALSO UNIVERSITY OF CHICAGO AND
OUR STUDY HAD 213 FAMILIES WHO
CONFIRMED CDH1 PATHOGE NIC
VARIANT.
NOW WE KNOW THAT SIGNET RING
CELLS ARE COMMON IN INDIVIDUALS
WITH CDH1 STAGE 1, WE REALLY DID
FOCUS ON STAGE 2 TO 4 AND
FOCUSED ON THOSE ANALYSIS FOR
TREATMENT.
SO THIS IS THE POPULATION, AN
AVERAGE OF 30 INDIVIDUALS PER
FAMILY AND AS FAR AS CANCER
HISTORY, TOWARDS THE BOTTOM
THERE WITH THE COMBINATION OF
FAMILY, MOST HAD BREAST AND
GASTRIC BUT WE SAW GASTRIC ONLY
FAMILIES AND BREAST CANCER ONLY
FAMILIES.
AND AS FAR AS THE PENETRANCE
ESTIMATES FROM OUR STUDY,
THINKING BACK TO THE CASE OF THE
11-YEAR-OLD, THE RISK TO DEVELOP
GASTRIC CANCER, UP TO AGE 30 WAS
A .2 PERCENT RISK.
SO AGAIN, STAGE 2 TO 4 AND THAT
IS THE SAME RISK FOR FEMALES.
WE ALSO FOUND THAT LIFETIME UP
RISK UP TO AGE 80, AROUND
10 PERCENT FOR MALE AND
6.5 PERCENT FOR FEMALES.
SO THESE RISK ESTIMATES ARE
SIGNIFICANTLY LOWER THAN THE
INITIAL PUBLISHED ESTIMATES AND
WHEN IT COMES TO, YOU KNOW, THE
IMPLICATIONS FOR GENETIC
COUNSELING FOR PATIENTS, WHAT IS
IMPORTANT TO KEEP IN MIND WHEN
TALKING TO PATIENTS, WE KNOW
CDH1 IS ASSOCIATED WITH GAS TRIC
CANCER RISK, MUCH HIGHER THAN
THE GENERAL POPULATION.
WE STILL DON'T UNDERSTAND WHY
STAGE 1 PROGRESSES OR HOW FAST
IT CAN PROGRESS AND BECAUSE OF
THAT, A GASTRECTOMY IS A SAFE
OPTION BUT ALSO SURVEILLANCE IS
A SAFE OPTION AS WELL, LOOKING
AT THERAPY, AND FAMILY HISTORY.
IF THERE IS A STRONG FAMILY
HISTORY OF GASTRIC CANCER, THEN
PERHAPS THEIR RISK IS A LOT
HIGHER.
THANK YOU.
>> THANKS, GRACE.
I AM GOING TO TRY TO BRING
EVERYTHING BACK TOGETHER.
SO A COUPLE OF IMPORTANT THINGS
THAT Dr. KORMAN SHOWED THAT
HOPEFULLY CAME THROUGH, GOING
BACK TO THE 11-YEAR-OLD.
WHEN YOU HAVE A CDH1 FINDING,
YOU DO AN ENDOSCOPY AND WHAT
Dr. KORMAN SHOWED IS THE
STOMACH LOOKS NORMAL, RIGHT?
AND THAT IS A PROBLEM BECAUSE WE
DON'T HAVE A WAY TO LOOK FOR
G ASTRIC CANCER IN THESE PEOPLE
IF THE STOMACH LOOKS NORMAL.
BUT THEN WHAT Dr. KIM SHOWED
YOU IS THIS KID HAD NOW TWO
ENDOSCOPIES WITH RANDOM BIOPSIES
SHOWING YOU THOSE LITTLE SIGNET
CELLS IN TWO PARTS OF THE
STOMACH AND WITH THE OTHER
PATIENT, IT WOULD SHOW YOU
94CIGNT RING CELLS WERE FOUND IN
THAT PATIENT WHICH ARE PRETTY
TYPICAL.
SO NOW OFF YOU HAVE A KID WITH
NO SPECIFIC HISTORY AND THESE
SIGNET CELLS IN THE STOMACH.
SO WHAT DO YOU DO?
WHY DID HE EVEN END UP HERE?
SO I WANT TO TELL YOU A LITTLE
BIT OF THE STORY ABOUT HOW HE
GOT HERE BECAUSE SOMEBODY MIGHT
ASK HOW DID WE BECOME A CENTER
OF EXPERTISE, WHICH WE ARE BY
THE WAY, FOR REMEMBER RED --
HEREDITARY GASTRIC CANCER.
WELL, GASDRIC CANCER IS RARE IN
THE U.S. SO WHERE WILL YOU GET
PATIENTS?
AND DOES THE NIH HAVE THE
EXPERTISE NECESSARY FOR PATIENTS
AND THEN ANOTHER THING I HEARD
WAS JEREMY, YOU ARE NOT A HIGH
VOLUME GASTRIC SURGEON, IT IS
NOT SAFE ANY WAY.
SO MANY OF HE IS WHO CARE FOR
GASTRIC CANCER AND CANCERS OF
THE UPPER GI TRACT, WE KNOW THAT
IT REQUIRES EXPERTISE IN CARING
FOR THESE PATIENTS AND IS
COORDINATED BY THESE GROUPS.
AND SO WE FELT WE CAN'T BRING
PATIENTS HERE IF WE CAN'T TAKE
CARE OF THEM AND THIS IS
PROBABLY THE FIRST MEETING OF
THE TEAM BACK IN THE DAY AND I
WOULD BALD BACK THEN TOO.
SO IN 2017 WE OPENED THIS
HEREDITARY GASTRIC CANCER
PROTOCOL AND I WILL SHOW YOU
THIS BECAUSE FRANKLY I WAS BLOWN
AWAY BY IT AND I WANT TO SHOW
YOU.
THIS IS OUR ACCRUAL.
IN 2017 WE OPENED AND YOU CAN
SEE IN JUST A FEW YEARS, OUR
CUMULATIVE ENROLLMENT JUST
SKYROCKETED.
AND TO THIS DATE, WE HAVE
ENROLLED OVER 700 PEOPLE.
NOW ON AVERAGE, IT IS ABOUT 7
NEW PATIENTS PER MONTH.
IT IS A NATURAL HISTORY STUDY.
NOT ALL OF THEM PHYSICALLY COME
HERE, BUT WE HAVE ABOUT 635
PATIENTS CURRENTLY ON STUDY THAT
COME FROM THROUGHOUT THE UNITED
STATES, CANADA, MEXICO, AS A LOT
OF STUDIES AROUND HERE DO.
WE NOW HAVE 300 FAMILIES AND
ABOUT 3/4 OF THEM HAVE
PATHOGENIC OR LIKELY PATHOGENIC
IN THE CDH1.
SOME OF THEM HAVE OTHER
SYNDROMES, CNA, ET CETERA.
SO I WASN'T THE HIGH GASITRIC
VOLUME SURGEON THEN BUT I AM NOW
AND Dr. KORMAN AND HIS TEAM DO
ABOUT 200 SURVEILLANCE
ENDOSCOPIES JUST FOR CDH1
ANNUALLY AND THEN WHAT I ALSO
TOLD YOU WAS THE RECOMMENDATION
THAT THESE PEOPLE JUST GET THEIR
STOMACHS REMOVED.
SO WE'RE NOT JUST TAKING OUT
STOMACHS, WE'RE TRYING TO SAVE
THEM AS WELL.
AND THE STRENGTH OF OUR RESEARCH
PROGRAM IS WE ARE THE ONLY ONE
OF IT KIND IN THE U.S.
I HAVE BEEN TO SLOAN KETTERING
AND MD ANDERSON AND THEY CAN'T
DO WHAT WE DO HERE.
OBVIOUSLY WE PROVIDE OUTSTANDING
CLINICAL CARE AND I WILL SHOW
YOU THE RESEARCH.
SO A COUPLE OF KEY TAKEAWAYS
FROM WHAT YOU HAVE SEEN FROM
Dr. KORMAN, Dr. KIM AND
GRACE MENTIONED IT AS WELL,
THESE SIGNET RING CELL LESIONS
ARE UBIQUITOUS WITH PEOPLE
WALKING AROUND WITH THIS CDH1
GERMLINE VARIANTS.
SO TO PROVE THAT, WE LOOKED AT
PEOPLE WITH CDH1 MUTATION, THEY
LOOK FINE, THEIR STOMACHS LOOK
NORMAL BUT THEY SAY DOC I WANT
MY STOMACH OUT BECAUSE I DON'T
WANT TO GET STOMACH CANCER.
SO WE LOOKED AT 150 OF THESE,
Dr. GALONIS DID THIS, FROM 18
AND THE OLDEST PERSON I HAVE
DONE IS 80 YEARS OLD AND GUESS
WHAT?
88PERCENT OF THOSE CASES, Dr.
KIM OR Dr. FASAYE FOUND
MULTIFOCAL STAGE 1SIGNET RING
CELL CARCINOMA WHICH WE SHOWED
YOU IN THOSE SAMPLES.
THE OTHER CASES WE LOOKED AT, WE
COULDN'T FIND CANCER BUT I THINK
THESE ARE FALSE NEGATIVES.
YOU CAN'T LOOK AT THE ENTIRE
STOMACH, WE WOULD BE DOING IT
FOR DAYS ON END AND THAT WOULD
PROBABLY KILL ME.
SO THE TAKEAWAY, 93 PERCENT OF
THESE ASYMPTOMATIC GROUP HAVE
OCCULT CANCERS.
THE OTHER THING IS IT IS I.R.S.
RESPECTIVE OF THEIR FAMILY
HISTORY.
GRACE SHOWED YOU THE HISTORY OF
THE 11-YEAR-OLD.
THERE WAS NO CANCER IN HIS
FAMILY.
SO THEN GRACE CAME TO ME AND THE
LAB AND SAID LET'S LOOK AT
BREAST CANCER, NO STOMACH CANCER
BUT HAVE THE CDH1 VARIANT.
15 PILL DECIDED I WILL HAVE MY
STOMACH OUT ANY WAY.
94PERCENT HAD EARLY STAGE
MULTITOKE CALL SIGNET STAGE 1
CELL LESIONS.
SO THERE IS SOMETHING ABOUT CDH1
LOSS OF FUNCTION MUTATION OR
MAYBE LOSS OF EXPRESSION IN
EPITHELIAL PRECURSORS IN THE
STOMACH THAT LEAD TO THE SIGNET
RING CELLS IRRESPECTIVE OF
FAMILY HISTORY.
IT IS IMPORTANT TO KNOW IF YOU
DON'T HAVE A CDH1 MUTATION, WE
WOULD NOT EXPECT TO FIND THESE
SIGNET RING CELLS IN YOUR
STOMACH.
Dr. KORMAN FOUND A PAPER FROM
TEXAS LOOKING AT 300 ENDOSCOPIES
AND YOU JUST DON'T FIND THOSE
CELLS IN PEOPLE WITHOUT THE
MUTATION.
I AM A SURGEON, I TAKE OUT A LOT
OF STOMACHS.
SEAHORSES DON'T HAVE STOMACHS,
BY THE WAY.
THE NEXT PEOPLE GOT ZEBRAS, WE
GET THE SEAHORSES.
SO WHAT IS THE LOSS OF REMOVING
THE STOMACH?
PEOPLE MAY SAY WELL YOU ARE
REMOVING THE STOMACH, THAT IS
GREAT.
THAT IS ANOTHER DOCTOR
OPERATING.
I AM THE ONE WITH THE BAD BACK.
SHE LOOKED AT 126 PEOPLE WE DID
A GASTRECTOMY ON AND THE ACUTE
MAJOR MORBIDITY IS 6 PERCENT AND
I WOULD ARGUE THAT IS PROBABLY
IN LINE WITH OTHER CANCER
THERAPIES BE IT COMBINED WITH
CHEMOTHERAPY OR RADIATION, ET
CETERA.
BUT WHAT Dr. GALONES LOOKED AT
AND WHAT WE PUBLISHED, WHEN YOU
LOOK AT PEOPLE WITH 24 MONTH
FOLLOW UPS, SEE HOW YOU ARE
DOING TWO YEARS LATER,
94 PERCENT HAD SOME FORM OF
CHRONIC COMPLICATIONS AND IT RAN
THE GAMUT.
DISPHASIA, BIOREFLUX WHICH IS
HORRIBLE FOR PATIENTS, AND THIS
IS A STUDY I AM NOT TALKING
ABOUT BUT DOCTOR GAMBLE DID THIS
DECISION-MAKING AND REGRET STUDY
PUBLISHED IN ANOTHER JOURNAL.
THE IMPACTS ON MENTAL HEALTH ARE
REALLY SIGNIFICANT AND WE HAVE
ONLY BEGUN TO SCRATCH THE
SURFACE ON THIS TOPIC, OKAY?
BUT TAKING OUT PEOPLE'S STOMACH
IS NOT LIKE OH GREAT, YOU
PREVENTED CANCER, WE'RE CAUSING
PROBLEMS.
SO LET'S GO BACK TO THE
11-YEAR-OLD, CDH1 GERMLINE
PATHOGENIC VARIANT, IF HE DIDN'T
HAVE THE GERMLINE YOU WOULD SAY
YOU ARE NOT GOING TO TAKE OUT
THE STOMACH BUT HE HAD A
PATHOLOG Y REPORT THAT SAID
CANCER AND THEY INITIATED
CHEMOTHERAPY.
WELL BASED ON WHAT WE SHOWED YOU
THAT THE SIGNET RING CELLS ARE
THERE IN ALL THESE PATIENTS AND
WE HAVE BEEN DOING SURVEILLANCE
ON HUNDREDS OF PEOPLE FOR YEARS
AT NIH AND NONE OF THEM
DEVELOPED MORE CANCER OR DIED OF
CANCER, ONLY TWO DEVELOPED STAGE
2 CANCER WHICH WE INTERVENED ON.
SO WE JUST FOLLOWED WITH CHEMO
THEIR. CHEMOTHERAPY.
WE INITIATED ENDOSCO PIC
SURVEILLANCE AT NIH BECAUSE MOST
PEOPLE DON'T WANT TO AND WE HAVE
BEEN FOLLOWING THEM AND MOST OF
THEM ARE NOT DEVELOPING CANCER.
AND OUR GOAL IS TO PREVENT
GASTRECTOMY.
SO I WILL SUMMARIZE HOW I THINK
OUR RESEARCH AFFECTED THIS CHILD
BUT I THINK IS IMPACTING LOTS OF
PEOPLE OUT THERE.
Dr. KIM, I SHOW HER PICTURE
BECAUSE SHE IS THE PATH
PATHOLOGIST FOR OCCULT SRC
PRESENT IN NEARLY ALL CDH1
VARIANT CARRIERS.
REMEMBER, WE'RE TAKING RANDOM
SHOTS OF THE STOMACH BUT THEY
ARE THERE AND THEN GRACE TOLD
YOU LIFETIME CANCER RISKS IS
PROBABLY LOWER THAN ORIGINAL
ESTIMATES OF LIKE 80 PERCENT,
RIGHT?
AND WE JUST OBSERVED PATIENTS IN
FAMILIES, WE SEE PEOPLE WITH
FAMILY MEMBERS IN THEIR 80s
WITH A CDH1 VARIANT ALIVE AND
WELL AT 80 AND NEVER DEVELOPED
CANCER.
SO CLEARLY WE'RE STARTING TO
SHOW A PICTURE OF THESE CANCERS
THAT ARE DETECTED IN PEOPLE THAT
MAYBE DON'T TURN INTO CANCER.
SO NOW THAT TELLS US WHY
SURVEILLANCE IS PROBABLY A
REASONABLE ALTERNATIVE TO
PROFYLACTIC GASTRONOMY AND AGAIN
I LIKE DOING GASTRECTOMIES BUT
THE CONSEQUENCES ARE SEVERE.
SO OUR CONCLUSIONS ARE MAYBE
THESE SIGNET RING CELLS THAT WE
FIND IN THE GERMLINE OF CDH1
CARRIERS ARE NOT CANCER BUT
PRECANCERS, RIGHT?
NOT ALL OF THEM ARE GOING TO
TURN INTO CANCER.
SO THAT LEADS TO THE RESEARCH
QUESTIONS AND I WILL TRY TO DO
THIS IN THE LAST FEW MINUTES.
WHAT ACCOUNTS FOR THIS DROPOFF?
WE FIND THE CELLS IN EVERYBODY
WITH THE MUTATION BUT NOT
EVERYBODY DEVELOPS CANCER.
WHY?
WHAT IS THE PHENOTYPE OF THOSE
LITTLE SIGNET RING CELLS, WHY
ARE THEY SO UNIQUE HOR OR HOW
ARE THEY DIFFERENT FROM ADVANCED
CANCER?
SO TIM IS A BIOLOGIST, HELPED ME
OUT IN THE LAB, HOPE HE DOESN'T
MIND.
WE STARTED THIS MANY YEARS AGO
AND THEN BEN FINISHED IT BUT WE
DID BULK INVESTIGATION OF THESE
SIGNET RING CELLS AND SHOWED
VERY SIMPLY THAT THE SRC
COMPARED TO NEP WHICH IS NORMAL
EPITHELIUM OF THE STOMACH HAD
SOME OBVIOUS CHANGES.
SO DOWN REGULATION OF NORMAL
GASTRIC GENES, THIS IS THE
PRETTY TON PUMP.
BUT GUESS WHAT?
THE SIGNET CELLS DIDN'T SHOW ANY
REGULATION OF WHAT YOU WOULD
CONSIDER TO BE CANCER, RIGHT?
WE DIDN'T SEE ANY DYSFUNCTION OR
UPREGULATION OF ONCOGENIC
PATHWAYS?
BEN SAID GEE, I SEE A LOT OF
CHANGES WITH IMMUNE SIGNALING, T
CELL, P CELL EXHAUSTION, STUFF
LIKE THAT SO THEN BEN PUBLISHED
THIS PAPER SAYING DOES THE
ENVIRONMENT INFLUENCE THE
BEHAVIOR OF THOSE SIGNET RING
CELLS?
IT MIGHT.
WE DON'T KNOW.
BUT THEN HE LOOKED AT THE
EXPRESS GENES AND SAID WE DON'T
SEE ANY UPREGULATION SIGNALING
BUT BOY TO WE SEE ENRICHMENT IN
C CELL SIGNALING, ET CETERA.
SO I WON'T GO INTO IT TODAY BUT
WE ARE USING THIS TO EXPLORE
CANCER PREVENTION IMIMMUNOLOGIC
STRATEGIES.
SO WE WERE GETTING READY TO PUT
TOGETHER THIS MANUSCRIPT, WE USE
THE HOT THING, THE NANOSTRING
PLATFORM TO LOOK AT THOSE SIGNET
RING CELLS COMPARED TO NORMAL
GASTRIC EPITHELIUM.
AND WE SAW OBVIOUSLY DOWN
REGULATION OF THE CDH1, Dr.
KIM SHOWED YOU WITH THE
CHEMISTRY.
AND THE SIGNET CELLS SHOW UP IN
YELLOW, AND THE CELLS OVER HERE
THAT SHOULD BE LIGHTING UP IN
BLUE ARE ABSENT SO IT IS LOST.
THAT IS GREAT SO THAT TELLS US
IT IS LIKE A INITIATING EVENT.
SO WHAT ELSE IS GOING ON? THE
CELLS ARE INVADING THE BASEMENT
MEMBRANE SO NOT SURPRISINGLY WE
SAW DID HE GO DAYS OF FCM, NO
DIFFERENCE IN EXPRESSION OF
MARKERS OF TUMOR PROLIFERATION
SO WE LOOKED AT PATIENTS WITH
MORE ADVANCED CANCERS I OPERATED
ON ON ANOTHER PROTOCOL.
AND GUESS WHAT?
NOW ALL OF A SUDDEN, YOU SAW
WHAT YOU EXPECTED TO SEE, RIGHT?
THE MORE ADVANCEDLESIONS,
GREATER THAN T2, THEY LOOKED SO
DIFFERENT THAN THE SIG NET
CELLS, SO WE SAW IN THE ADVANCED
CANCERS THE UPREGULATION OF
MYCO, OR MET, BUT THEY WEREN'T
THERE IN THE SIGNET CELLS.
OKAY THE THING IS ACTING FUNNY
SO IT MUST BE TIME TO END.
SO TO SUMMARIZE THIS ANALYSIS SO
FAR, THESE CDH PATIENTS START
HERE, THEY ARE HETEROZYG OUS AND
WHY THEY REAR THEIR UGLY HEAD,
WE DON'T KNOW.
THEY DON'T REALLY ACT LIKE
CANCERS AND THE ADVANCED CANCERS
CLEARLY LOOK DIFFERENT AND WE
NEED TO FIGURE OUT WHAT IT IS OR
WHY IT IS THAT THEY DO THAT.
SO TAKEHOME MESSAGE, 91 PERCENT
OF THE PATHOGENIC CARRIERS HAVE
THESE SIGNET CANCER CELLS HIDING
IN THEIR STOMACHS BUT THE
GASTRIC ACTIVE CANCER IS LOW,
AND WHEN I PERFORM THE
GASTRECTOMY, IT HAS CHRONIC
SEGUELAE AND THE EARLY SIGNET
RING CELL LESIONS ARE
NONOBLIGATED CANCERS.
SO OUR RESEARCH HAS IMPACT ON
INDIVIDUALS AND WE ARE OFFERING
HOPE TO PATIENTS WHO WERE TOLD
GASTRIC CANCER IS ALL BUT
CERTAIN AND GASTRECTOMY IS THE
ONLY OPTION.
HERE AT THE NIH AND PEOPLE STILL
WITH ME, DESPITE THE CLINICAL
CENTER AT NIH, WE LIKE TO TALK
ABOUT SOME THINGS THAT GET IN
OUR WAY, WE CAN STILL DO
MEANINGFUL WORK BUT WE CAN'T
TAKE IT FOR GRANTED.
IT REQUIRES WE SAY YES MORE THAN
WE SAY NO AND OF COURSE WE CAN
DO THAT, NOT NAH, WE CAN'T
REALLY DO THAT, RIGHT?
AND IT MEANS WE TEND TO PEOPLE
BECAUSE THEY ARE THE ONES THAT
MAKE THE INSTITUTION.
WE HAVE TO GROW PEOPLE, WE HAVE
TO NURTURE THEM AND ALL KOPT
PWAOUGSZ ARE IMPORTANT
REGARDLESS OF THE INDIVIDUALS'
TITLE OR STATUS.
SO WITH THAT I WANT TO THANK
EVERYBODY ON MY TEAM AND THE
EXTENDED TEAM, THANK YOU VERY
MUCH FOR YOUR TIME AND ATTENTION
AND SORRY I WENT A MINUTE OR TWO
MINUTES OVER.
[APPLAUSE]
>> THANK YOU FOR THIS PHENOMENAL
TALK.
JUST GOING A LITTLE BIT OVER, WE
WILL ASK IF ANYBODY HAS A
QUESTION TO EITHER DIRECTLY
FORWARD IT TO JEREMY OR MYSELF
AND THEN WE WILL WRAP IT UP FOR
TODAY.
THANK YOU ALL FOR BEING HERE
VIRTUALLY AND THANKS FOR DOING
WHAT YOU ARE DOING AS THE
MULTIDISCIPLINARY TOO MANY AND
-- TEAM AND ONE OF THE MAJOR
STRENGTHS OF OUR HOSPITAL.
THANK YOU.