Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
OUR PRESENTERS TODAY INCLUDE DR.
CHRISTINA ANNUNZIATA, SENIOR
VISITOR IN WOMEN'S MALIGNANCIES
BRANCH CENTER FOR CANCER
RESEARCH NCI.
DR. ELAINE JAFFE, NIH
DISTINGUISHED INVESTIGATOR,
LABORATORY OF PATHOLOGY, ALSO AT
NCI.
DR. ASHKAN MALAYERI, LEAD
RADIOLOGIST FOR BODY MRI NIH
CLINICAL CENTER.
DR. DIANENA BAN BIANCHI, NHGRI
AND DIRECTOR OF THE NATIONAL
INSTITUTE OF CHILD HEALTH AND
HUMAN DEVELOPMENT.
AND MS. AMY TURRIFF, GENETIC
COUNSELOR IN THE CENTER FOR
PRECISION HEALTH RESEARCH NHGRI.
WE ARE GOING TO HEAR TODAY ABOUT
WHAT NOT TO EXPECT WHEN
EXPECTING, THE IDENTIFY STUDY.
WITH THAT I'LL HAND IT OVER.
>> THANKS SO MUCH, DR. BAROCHIA.
TODAY WE WILL PRESENT TO YOU A
CASE WHICH IS A PATIENT WHO
ENROLLED ON OUR IDENTIFY STUDY.
NEXT SLIDE.
JUST TO NOTE THAT NONE OF US
HAVE FINANCIAL DISCLOSURES.
THE OUTLINE OF OUR PRESENTATION
TODAY WILL START WITH THE CASE
PRESENTATION, GO THROUGH
IMAGING, THEN PATHOLOGY, THEN DO
A CLINICAL FOLLOW-UP AND THEN A
DISCUSSION OF THE BACKGROUND AND
FUTURE RESEARCH FOR THE STUDY.
SO THE CASE PRESENTATION STARTS
WITH A 31-YEAR-OLD WOMAN, THIS
WAS HER FIRST PREGNANCY.
SHE WAS OTHERWISE HEALTHY
WITHOUT ANY OTHER SYMPTOMS.
IN APRIL 2021 AT 12 WEEKS
PREGNANT SHE UNDERWENT
NON-INVASIVE PRE-NATAL TEST OR
NIPT THAT SHOWED MON SEWMY 1 AND
TRY SEWMY TWO.
I WILL GET INTO THOSE DETAILS IN
A BIT.
IN MAY OF 2021, WHEN SHE WAS 16
WEEKS PREGNANT SHE UNDERWENT
AMNIOCENTESIS AND FOUND TO HAVE
NORMAL FETAL KARYOTYPE.
SO WHAT IS THE NIPT TEST?
THERE ARE SEVERAL TESTS FOR
PRE-NATAL TESTS FOR FETAL
AANYPLOIDIES.
WE ARE LOOKING FOR COMMON FETAL
ANE UPLOIDE IRKS SERKS.
THESE ARE INCREASED RISK OF
HAVING THESE WITH INCREASING
MATERNAL AGE BUT ALSO OTHER
FACTORS.
THE SCREENING TEST THAT ARE
AVAILABLE FOR FETAL ANEUPLOIDY
INCLUDE FIRST TRIMESTER, IS 10
TO 14 WEEKS HAVE A SERUM ANOLYTE
TEST DRAWN WHICH IS THE BETA HCG
AND THE PATH A AND ALSO
ULTRASOUND.
AT 15 TO 22 WEEKS, SECOND
TRIMESTER WOMEN WITH UNDERGO
QUADRUPLE SCREEN WHICH INCLUDES
THE BETA HCG AFP, ESTRADIOL AND
DIA.
THROUGHOUT THE PREGNANCY THOUGH
FROM TEN TO 40 WEEKS PATIENTS
WITH CAN UNDERGO THE
NON-INVASIVE PRE-NATAL TEST
WHICH IS SELF RADON -- CELL FREE
DNA.
SO THE NIPT TEST IS AS I
MENTIONED A SCREENING TEST FOR
FETAL CHROMOSOMAL ABNORMALITIES
OR ANEUPLOIDY, IT HAS A HIGHER
POSITIVE PREDICTIVE VALUE THAN
SERUM ANOLYTE TESTING.
THE OTHER BENEFIT IS IT CAN
IDENTIFY THE SEX OF THE BABY SO
THIS MAKES IT A VERY ATTRACTIVE
TEST FOR BOTH PREGNANT WOMAN,
PREGNANT FAMILY AND THE
PHYSICIAN TREATING THE PATIENT.
THIS TEST CAN BE OFFERED TO ALL
PREGNANT PATIENTS REGARDLESS OF
AGE.
IT IS AS I MENTIONED A CELL FREE
DNA TEST SO IT IS BASICALLY
LOOKING FOR THE FETAL FRACTION
OF CELL FREE DNA IN THE MATERNAL
CIRCULATION.
CELL FREE DNA FROM FETUS CAN BE
DETECTED STARTING AT 9 TO 10
WEEKS GESTATION, AND IT DOES
INCREASE THROUGHOUT THE
PREGNANCY.
BY END OF THE PREGNANCY IT CAN
BE AS MUCH AS 13% OF THE TOTAL
CELL FREE DNA IN THE MATERNAL
BLOOD.
WHEN ONE OF THESE SCREENING
TESTS IS ABNORMAL, A WOMAN WILL
THEN PROCEED TO A DIAGNOSTIC
TEST.
SO THE DIAGNOSTIC TEST CAN BE AN
AMNIOCENTESIS OR CORIONIC
SAMPLING THAT CAN LOOK AT FETAL
KARYOTYPES THE CELLSOMES IN MORE
DETAIL.
WHEN THE RESULTS OF THE NIPT
TESTS ARE NON-REPORTABLE, THE
LABORATORY THIS MEANS THE
LABORATORY IS REALLY UNABLE TO
RETURN THE FETAL RISK
ASSESSMENT.
THIS ACTUALLY CAN MEAN THAT
THERE IS ACTUALLY INCREASE RISK
OF FETAL CHROMOSOMAL
ABNORMALITIES BUT THESE MIGHT BE
OTHER THAN THE 13, 18 OR 21 THAT
IS INVOLVED.
SO IF IF THE WOMAN UNDERGOES A
DIAGNOSTIC TEST AFTER
NON-REPORTABLE NIPT, AND THE
DIAGNOSTIC TEST THEN SHOWS
NORMAL FETAL CHROMOSOMES, THERE
IS NO STANDARD RECOMMENDATIONS
FOR WHAT TO DO FOR THE MATERNAL
EVALUATION.
WHAT'S GOING ON IN THE MATERNAL
CIRCULATION.
NEXT SLIDE.
SO AS I MENTION R BP AT 12 WEEKS
PREGNANT UNDERWENT NIPT AND HER
RESULTS WERE INITIALLY DELIVERED
AS NON-REPORTABLE.
SO THIS IS WHAT SHE GOT
RETURNED, SHE HAD NORMAL 13, 18
AND 21 BUT THERE WAS A LITTLE
SORT OF FINE PRINT BOX THERE
SAYING THAT THESE REGIONS ARE
NEGATIVE BUT THESE MIGHT REFLECT
OTHER CHROMOSOMAL FETAL
ABNORMALITIES, PLACENTAL AND/OR
THE PATIENT HERSELF MAY BE DUE
TO MATERNAL CONDITIONS OR MAYBE
A FALSE POSITIVE.
SO BASICALLY THEN THE LITTLE
FINE PRINT UNDER THAT IS THAT
GENETIC COUNSELING IS
RECOMMENDED.
SO WHEN WE INQUIRED A LITTLE BIT
MORE WHEN SHE INQUIRED A LITTLE
BIT MORE ABOUT WHAT WERE THESE
OTHER FINDINGS, TURNED OUT WHAT
THEY HAD FOUND ON THE SCREENING
TEST WAS A MONOSOMY OF
CHROMOSOME 1 AND TRISOMY OF
CHROMOSOME 2.
SO SHE DID UNDERGO AMNIOCENTESIS
AT 16 WEEKS PREGNANT AND THAT
SHOWED A NORMAL FETAL KARYOTYPE.
SO BASED ON THAT SHE WAS
ELIGIBLE TO ENROLL IN OUR STUDY,
THE IDENTIFY STUDY, WHEN SHE WAS
28 WEEKS PREGNANT.
SO THE IDENTIFY STUDY WE HAVE
OPEN HERE IN THE CLINICAL CENTER
IS 19C 0132, IT IS AN NCI STUDY.
AND IT IS CALLED INCIDENTAL
DETECTION OF MATERNAL NEOPLASIA
THROUGH NON-INVASIVE CELL FREE
DNA ANALYSIS.
NEXT SLIDE.
JUST BRIEFLY TO EMPHASIZE THIS
WAS A HEALTHY PATIENT SHE HAD
REALLY NO OTHER PAST MEDICAL
HISTORY.
SHE HAD FAMILY HISTORY
SIGNIFICANT WITH MATERNAL
GRANDMOTHER ENDOMETRIAL EARLY
STAGE CANCER LIST RECKTOMY BUT
NO FURTHER ADJUVANT THERAPY.
A PATERNAL GRANDFATHER HAD LUNG
CANCER AFTER HEAVY SMOKING
HISTORY, AGAIN EARLY STAGE AND
HAS BEEN IN REMISSION 10 YEARS.
REST OF HISTORY WAS NEGATIVE,
REVIEW OF SYSTEMS WAS NEGATIVE,
ASYMPTOMATIC.
LABORATORIES SHOW MILD ANEMIA
PREGNANCY 11.5 HEMOGLOBIN
OTHERWISE NORMAL.
SO NOW I WILL TURN IT OVER TO
DR. MALAYERI TOLL DISCUSS MRI
FINDINGS.
>> THANK YOU VERY MUCH.
I WILL GO OVER THE MRI AND WHAT
WE DO FOR SCREENING PATIENTS FOR
HIGH RISK AT NIH.
WE HAVE A LOT OF EXPERIENCE WITH
THESE PATIENTS AND DOING WHOLE
BODY MRI.
I WILL SPECIFICALLY TALK ABOUT
WHAT WE DO IN PATIENTS WHO ARE
ENROLLED IN IDENTIFY STUDY.
THIS IS AN OUTLINE OF SOME OF
THE SEQUENCES WE RUN IN THIS
PATIENTS, AS YOU CAN SEE ON THE
LEFT THERE ARE TWO CHORONAL
IMAGES STITCHED TOGETHER TO GIVE
A SEAMLESS VIEW OF PATIENT AS IF
THE PATIENT IS STANDING IN FRONT
OF YOU.
AND WE SCAN THE ENTIRE BODY FOR
ANY ABNORMAL SIGNAL.
AND IN ORDER TO GET A MORE
DETAIL LOOK INSIDE BODY, WE
ACQUIRED THE AXIAL IMAGES ON THE
RIGHT SIDE OF THE SCREEN, T 1
SEQUENCES DESIGNED TO GIVE A LOT
OF ANATOMICAL INFORMATION.
AND AXIAL DWI IS CONSIDERED A
FUNCTIONAL IMAGE THAT IS VERY
SENSITIVE TO DETECT MALIGNANCY.
ALL THESE SCANS ARE DONE ON A
LOW POWER SCANNER THAT IS 1.5
TESLA SCANNER COMPARED TO 3T
SCANS THAT WE HAVE AND HAY TAKE
APPROXIMATELY 45 MINUTES TO
ACQUIRE.
SO COUPLE OF WORDS FOR PATIENTS
WHO ARE PREGNANT UNDERGOING MRI.
FIRST IS STRENGTHS OF MAGNETIC
FIELD.
SOME OF THESE FROM MESH COLLEGE
OF RADIOLOGY MANUAL ON MRI
SAFETY.
WE USE MRI ROUTINELY FOR
PATIENTS WHO ARE PREGNANT TO
DEMONSTRATE FETAL ABNORMALITIES
OR ANSWER CLINICAL QUESTIONS,
THERE ARE NO CLINICAL DATA
SHOWING EXPOSURE TO MR HAS
DELETERIOUS AFFECTS ON
DEVELOPING FETUS.
IF PREGNANCY IS ESTABLISHED
DECISION TO PROCEED WITH A
NON-CONTRAST MR STUDY AT 1.5 T
SCANNER SIMILAR TO ONE WE USE,
SHOULD BE BASED ON MEDICAL
BENEFIT WEIGHTED AGAINST UNKNOWN
POTENTIAL REIS.
MRI IS VERY SAFE IN PREGNANCY
AND DONE ON ROUTINE BASIS.
NEXT SLIDE.
HOWEVER CONTRAST IS ANOTHER
ISSUE IN MR AND WE DON'T USE
CONTRAST FOR PROTOCOL AND THERE
IS TYPE OF CONTRAST WE USE FOR
MRI IS A CONTRAST AGENT.
THESE HAVE SHOWN TO CROSS THE
PLACENTA, BLOOD BARRIER AND GET
INTO THE FETUS CIRCULATION.
MRI CONTRAST PATIENTS SHOULD NOT
BE USED TO PREGNANT PATIENTS.
AS A RESULT THERE IS WIDESPREAD
CONSENSUS THAT AVOIDING GAD LYNN
YUM BASED CONTRAST AGENTS IN
PREGNANCY IS PRUDENT.
GOING BACK TO OUR PATIENTS,
THESE ARE IMAGES WE DISCUSSED
BEFORE.
AS YOU CAN SEE THE PATIENT IS
PREGNANT WITH A FETUS IN THE
UTERUS AND YOU CAN SEE THE
YELLOW ARROW IS POINTING TOWARDS
SIGNAL ABNORMALITY IN THE
INTERIOR MEDIA STEINUM, IT
APPEARS IN THE STY NUMBER IN THE
ANTERIOR WEIGHTED IMAGES.
WE REQUIRE AXIAL IMAGES NEXT
SLIDE PLEASE.
AND HERE YOU CAN SEE CLEARLY
THAT THERE IS A SIGNAL
ABNORMALITY IN THE ANTERIOR
MEDIA STINUM CLOSE TO THYMUS ON
THE STIR AND T 1 IMAGES AND ON
AXIAL DWI IMAGE YOU CAN SEE THIS
SHOWING INCREASED SIGNAL.
DWI IMAGES ARE AS I SAID BEFORE,
FUNCTIONAL IMAGES AND THEY LOOK
AT MOTION OF WATER MOLECULES IN
MICROENVIRONMENTMENT SO IF HIGH
CYTOPLASMIC NUCLEUS RATIO OR
CELL WALS ARE NOT FUNCTIONING
PROPERLY SUCH ASTHMA LEG
FANTASTIC TISSUE, YOU WOULD END
UP WITH INCREASE SIGNAL ON DWI
IMAGE.
>> SO THIS PATIENT HAD OPTED TO
UNDERGO FIRST WORK UP AFTER
DELIVERY SO IN OCTOBER 2021 SHE
DELIVERED HEALTHY BABY AND IN
NOVEMBER OF 2021 SHE RETURNED TO
NIH AND UNDERWENT A PET CT SCAN.
>> SO WE PERFORM THE FDG PET
AFTER PREGNANCY AND AS YOU CAN
SEE HERE THERE IS A ON THE IMAGE
ON THE LEFT THERE IS AVID FDG
UPTAKE IN MASS WE SAW BEFORE.
AND IMAGE ON THE RIGHT WHICH IS
A MIP IMAGE YOU CAN SEE INCREASE
ACTIVITY IN THE MASS NICELY HERE
BUT YOU DON'T SEE ANY OTHER
SORTS OF -- ANY OTHER ACTIVITY
THROUGHOUT THE BODY.
THERE IS A LOT OF ACTIVITY IN
THE BREAST TISSUE BECAUSE
PATIENT IS POSTPARTUM.
SO ON DECEMBER 21, PATIENT
UNDERWENT SURGICAL BIOPSY AND
RESECTION FOR DIAGNOSIS.
I WILL TURN IT OVER TO DR. JAFFE
TO GO OVER PATHOLOGY.
THANK YOU.
>> SO AS YOU HAVE HEARD, THE
PATIENT HAD AN INTERIOR
MEDIASTINAL MASS LEADING TO
SURGICAL EXCISION OF THYMUS
GLAND.
THE WEIGHT WAS 49 GRAMS,
SOMEWHAT ENLARGED FOR AN
INDIVIDUAL AT HER AGE.
THE THYMUS WAS LARGELY NORMAL
BUT A SINGLE MASS SEEN WITHIN
THE THYMUS MEASURING
APPROXIMATELY 3 BY
3-CENTIMETERS.
HERE YOU CAN SEE THE NORMAL
THYMUS GLAND WITH BOTH CORTICAL
AND MEDULLARY AREAS.
AND WITHIN THE THYMUS THERE WAS
A SINGLE MASS, THE MASS WAS
LIMITED BY FIBROUS TISSUE.
DELIMITED BY FIBROUS TISSUE AND
NO EXTENSION BEYOND THE THYMUS
GLAND.
NEXT PLEASE.
HERE AT HIGHER POWER WITHIN THE
MASS LESION YOU CAN SEE SHEETS
OF LARGE LYMPHOID CELLS.
THERE ARE FREQUENT MITOTIC
FIGURES AS NOTED BY THE RED
ARROW.
IMMUNOHISTOCHEMICAL STUDIES
SHOWED CD 20 EXPRESSION
INDICATING THAT THIS WAS A B
CELL LYMPHOMA, THE TUMOR WAS
POSITIVE FOR BCL 6 AND CD 30.
THE OVERALL MORPHOLOGY AND
IMMUNOPHENOTYPE WAS
CHARACTERISTIC OF PRIMARY
MEDIASTINAL B CELL LYMPHOMA
REFERRED TO AS PRIMARY MEDIA
MEDIASTINAL, AND CLASSIC
HODGKIN'S LYMPHOMA OF THE
NODULAR TYPE, SHARE MANY
FEATURES IN COMMON BOTH DISEASE
ARE MORE COMMON IN FEMALES THAN
MALES AND TYPICALLY PRESENT IN
ADOLESCENCE OR YOUNG ADULTS.
THE CLASSIC PRESENTATION IS A
MEDIASTINAL MASS WITH OR WITHOUT
INVOLVEMENT OF CLAVICULAR LYMPH
NODES.
TUMORS SHARE COMMON CYTOGENETIC
ABNORMALITIES INCLUDING GAINS AT
9P 24 AND GAINS AT 2P 16.
INTERESTINGLY AS YOU HEARD, THIS
PATIENT HAD EVIDENCE OF
ANEUPLOIDY ON CHROMOSOME 2 IN
HER PRE-CLINICAL --
PRE-PREGNANCY TEST.
BOTH DISEASES SHOW SIMILAR
PATTERN OF GENE EXPRESSION WITH
ACTIVATION OF NF KAPPA B PATHWAY
AND BOTH LYMPHOMAS ARISE FROM B
CELL.
TURN BACK TO DR. ANNUNZIATA FOR
FURTHER FOLLOW-UP.
>> THANK YOU.
TO CONTINUE WITH FOLLOW-UP ON
THIS PATIENT, SHE WAS DIAGNOSED
WITH PRIMARY MEDIASTINAL
LYMPHOMA, LIMITED STAGE WHERE IT
WAS CONTAINED IN ONE POTENTIAL
RADIATION FIELD.
ADVANCE STAGE DISEASE IF SHE HAD
THAT WOULD HAVE BEEN DIAGNOSED
-- WOULD HAVE BEEN GREATER THAT
THAN TEN CENTIMETERS FOR
WIDESPREAD.
TYPICAL TREATMENT FOR LIMITED
STAGE DISEASE IS OUR TOP
CHEMOTHERAPY FOR SIX CYCLES PLUS
FIELD RADIATION OR DOSES
ADJUSTED EPOCR FOR 6 TO 8 CYCLES
WITHOUT RADIATION.
OUR PATIENT BECAUSE SHE WAS
DIAGNOSED SO EARLY, EXCUSE ME GO
BACK.
BECAUSE SHE WAS DIAGNOSED EARLY
SHE HAD THE MASS SURGICALLY
REMOVED, FOR DIAGNOSTIC PURPOSES
SHE IS UNDERGOING FOUR CYCLES OF
TOP CHEMOTHERAPY, ABBREVIATED
DUE TO TEXT OF HER DISEASE.
I WILL TURN IT OVER TO DR.
BIANCHI.
>> THANK YOU, DR. ANNUNZIATA.
SO WE TITLED THIS WHAT NOT TO
EXPECT WHEN YOU ARE EXPECTING
BECAUSE WE CERTAINLY DIDN'T
EXPECT THAT A ROUTINE PRE-NATAL
SCREEN FOR ANEUPLOIDY WOULD
DETECT CANCER.
STEPPING BACK, CELL FREE DNA
SEQUENCING OF MATERNAL PLASMA IS
ROUTINELY OVERRED TO PREGNANT
WELL AS DR. ANNUNZIATA SAID.
THE DIFFERENCE IS THAT MANAGED
CARE INSURANCE PLANS PAY FOR THE
TEST GENERALLY IF THE WOMAN IS
HIGH RISK AND WE ARE MOVING OVER
TO SOME SCENARIOS TO HAVE IT
PAID FOR BY INSURANCE FOR WOMEN
OF LOW RISK OR GENERAL RISK.
AS YOU HEARD FROM DR. ANNUNZIATA
EARLIER, POSITIVE SCREENS REALLY
REQUIRE DIAGNOSTIC CONFIRMATION.
SOME WOMEN CHOOSE NOT TO DO THAT
BUT THAT IS THE OFFICIAL
RECOMMENDATION.
WHAT WE WILL BE TALKING ABOUT
HERE, THE FALSE POSITIVE RESULTS
WHICH MEANS THAT THE RESULTS
WERE ABOUT NORMAL OR
NON-REPORTABLE, AND YOU HAVE
NORMAL FETAL DIAGNOSTIC
KARYOTYPE OR MICROARRAY OBTAINED
FROM AMNIOCENTESIS OR CHORIONI
SAMPLING.
BOTH MOTHER AND FETUS PRODUCE
CELL FREE DNA FROM APOT TOPIC
CELLS.
WE ARE ALL PRODUCING CELL FREE
DNA AND CIRCULATING IN OUR BLOOD
RIGHT NOW.
IN ADULTS THE DNA IS ORIGINATING
FROM THE BONE MARROW.
WE SAY THAT THIS IS A FETAL
SCREENING TEST, IT IS A
PLACENTAL SCREENING TEST.
SO WHEN WE DO HAVE ABNORMAL
RESULTS IT IS REALLY GENERALLY
ORIGINATING ON PLACENTA, IF
FETAL IN ORIGIN.
THE TESTING IS DONE VIA
MASSIVELY PARALLEL SEQUENCING
AND THAT IS PERFORMED ON A MIXED
DNA SAMPLE.
SO YOU ARE TAKING BLOOD, REGULAR
PERIPHERAL BLOOD SAMPLE, AND THE
AVERAGE SAMPLE AS YOU HEARD FROM
DR. ANNUNZIATA IS GOING TO
CONTAIN SOMEWHERE AROUND 10%
FETAL PLACENTAL DNA, REMAINDER
IS MATERNAL CELL FREE DNA AND
YOU ARE SEQUENCING BOTH AT THE
SAME TIME.
THEREFORE YOU CAN'T REALLY
DISTINGUISH BETWEEN MATERNAL DNA
AND THE FETAL DNA UNLESS FETUS
IS MALE, IN THAT CASE THE Y
CHROMOSOMAL SEQUENCES ARE COMING
FROM MALE FETUS AND ALSO
POSSIBLE THE FETUS HAS UNIQUE
SINGLE NUCLEOTIDE POLYMORPHISMS.
THAT CAN BE USED TO MEASURE THE
FETAL FRACTION.
NEXT SLIDE.
THERE ARE BASICALLY TWO METHODS
OF NON-INVASIVE PRE-NATAL
TESTING.
ONE IS THE RANDOM GENOME WIDE
SEQUENCING THIS IS LIGHT GOING
-- LIKE GOING FISHING WITH A
GIANT NET AND YOU ARE THROWING
THE NETTED OUT AND CAPTURING
EVERYTHING WITHIN THAT NET.
SO THE CELL FREE DNA IN MATERNAL
BLOOD IS RANDOMLY SAMPLED,
SEQUENCED, MAPPED TO SPECIFIC
CHROMOSOMES, THEN NUMBER OF TAGS
THAT MAP TO CHROMOSOMES ARE
COUNTED RELATIVE TO A REFERENCE
GENOME.
IF THERE ARE DIFFERENCES, TOO
MUCH OF ONE CHROMOSOME OR TOO
LITTLE THAT TRIGGERS A FLAG FOR
ANEUPLOIDY.
IN GENERAL THE MOST COMMON
ITERATION OF TEST ONLY RESULTS
FROM 13, 18, 21, X AND Y ARE
MADE AVAILABLE ALTHOUGH THE
TESTING IS DONE ON THE ENTIRE
GENOME, REMAINDER OF THE RESULTS
ARE MASKED BUT THAT MASK CAN BE
LIFTED AS IT WAS THIS CASE.
A DIFFERENT WAY THE TEST IS DONE
IS USING TARGETED OR SINGLE
NUCLEOTIDE POLYMORPHISM OR SNP
BASED SEQUENCING.
THAT'S LIKE FISHING WITH A
FISHING ROD AND BLUE DOTS
REPRESENTING BAIT AND THE BAIT
WILL ATTRACT SPECIFIC SEQUENCES
FROM SPECIFIC CHROMOSOMES THAT
ARE AMPLIFIED AND SEQUENCED.
MOTHER IN THIS CASE IS USED AS
REFERENCE AND DIFFERENTS ARE
CALCULATED BETWEEN MATERNAL AND
FETAL PLACENTAL DNA SEQUENCE TO
IDENTIFY THE PREGNANCIES THAT
ARE AT RISK FOR ANEUPLOIDY.
NOW, HERE IN THIS STUDY WE ARE
INTERESTED IN THE UNUSUAL NIPT
RESULTS.
EITHER OF THESE METHODS,
LABORATORIES MAY ENCOUNTER
UNUSUAL RESULTS THAT INTERFERE
WITH THE BIOINFORMATICS
ALGORITHMS THAT ARE LOOKING AT
THE RATIOS BETWEEN THE
CHROMOSOME OF INTEREST AND THE
REFERENCE CHROMOSOME.
AND WHEN THERE IS THIS
UNEXPECTED ABNORMALITY, THAT
WILL TRIGGER A NON-REPORTABLE
RESULT.
IF IT IS USING THE GENOME WIDE
TESTING THEY CAN UNMASK THE
REMAINDER OF THE RESULTS, THIS
WILL BE TRIGGERED BY
NON-REPORTABLE RESULTS AND
THEREFORE HAY WILL LOOK AT THE
ENTIRE WHOLE GENOME SEQUENCING.
THEY WILL OFFICIALLY SAY THERE
IS A NON-REPORTABLE RESULT
BECAUSE THERE IS NO STANDARD WAY
OF COMMUNICATING RESULTS BUT
OFTENTIMES THERE IS A VERBAL
CONVERSATION BETWEEN LABORATORY
AND THE CLINICIAN.
IN THE SNP PHASE RESULTS THEY
USUALLY SAY THERE'S ATYPICAL
RESULT BEYOND SCOPE OF THE TEST.
USUALLY THEY SAY A REPEAT SAMPLE
IS NOT RECOMMENDED.
NOW ALL THIS IS A RELATIVELY
RECENT PROBLEM, THE VERY FIRST
DOCUMENTATION OF THE PRESENCE OF
PLACENTAL DNA IN MATERNAL PLASMA
WAS ONLY IN 1997.
IT WAS REALLY WITH THE
DEVELOPMENT AND AVAILABILITY OF
MASSIVELY PARALLEL SEQUENCING
MACHINES, THAT WE COULD PERFORM
LARGE SCALE CLINICAL STUDIES.
THESE RESULTED IN VALIDATION
TESTS IN 2010, 2011 SHOWING
FIRST YOU COULD RELIABLY TEST
TRISOMY 21, THAT LED TO THE
FIRST COMMERCIAL AND CLINICAL
AVAILABILITY OF THE TESTING ONLY
A DECADE AGO.
IT FIRST STARTED IN CHINA AND
HONG KONG, WENT TO THE UNITED
STATES, THEN TO EUROPE THEN TO
THE REST OF THE WORLD.
I LIKE TO SAY IT IS THE MOST
SUCCESSFUL GENOMIC TEST IN
MEDICAL HISTORY BECAUSE REALLY
WITHIN A SHORT PERIOD OF TIME
NOT ONLY HAVE THE TESTS BEEN
VALIDATED BUT ALSO PAID FOR BY
MANAGED CARE INSURANCE AND BE MY
STATE MEDICAID PROGRAMS.
THE SUCCESS OF SCREENING FOR
ANEUPLOIDY LED TO EXPANSION OF
THE MENU, WE ARE NOW SCREENING
FOR SEX CHROMOSOME ANEUPLOIDY'S
AS WELL AS COMMON MICRODELETIONS
SUCH AS DELETION ON THE LONG ARM
OF 22 ASSOCIATED WITH GEORGE
SYNDROME.
IN 2013 AS YOU WILL SEE IN A
MOMENT, WE HAD THE FIRST REPORT
OF DISCORDANT RESULT THROUGH TO
MATERNAL MALIGNANCY.
MORE RECENTLY SEVERAL LABORATORY
ARE REPORTING RARE AWESOMAL
TRISOMIES FOR RATS.
AS I SAID, THE VERY FIRST
IMPLEMENTATION OF THE TEST
CLINICALLY WAS THE LATE STAGES
OF 2011 AND TWO YEARS LATER WE
BEGAN TO SEE ARTICLES SUCH AS
THIS ONE, CLAIMING THAT THERE
ARE MANY FALSE POSITIVE CASES OF
NIPT AND MAYBE WE SHOULDN'T BE
SO FAST TO INCORPORATE THIS TEST
INTO CLINICAL CARE.
NEXT SLIDE PLEASE.
TURNS OUT THERE WASN'T ANYTHING
WRONG WITH THE TEST, THE TEST
WAS ACTUALLY GOING BEYOND WHAT
IT WAS INITIALLY EXPECTED TO DO.
IT IS SO SENSITIVE THAT IT
DETECTS ALTERNATIVE BIOLOGICAL
EXPLANATIONS FOR THE FALSE
POSITIVE RESULTS.
REALLY NOT FALSE POSITIVE JUST
DETECTING SOMETHING OTHER THAN
WHAT WAS EXPECTED.
SO IF YOU ARE TALKING ABOUT THE
FETUS AND PLACENTA, THAT 10% OF
DNA, YOU CAN DETECT
ABNORMALITIES THAT ARE COMBINED
TO THE PLACENTA SUCH AS COMBINED
PLACENTAL MOI SAKISM, YOU CAN
DEFINE WHERE IT HAS PARTLY
NORMAL CHROMOSOMES AN PARTLY
ABNORMAL CHROMOSOMES.
YOU CAN ALSO HAVE A SITUATION
WHERE THERE WAS INITIALLY TWIN
CONCEPTION BUT ONE TWIN HAS A
CHROMOSOME ABNORMALITY AND THAT
LED TO A SPONTANEOUS MISCARRIAGE
OF THE PLACENTA MAY STILL BE
RELEASING DNA INTO MATERNAL
CIRCULATION SO WHAT YOU ARE
DETECTING IN THAT CASE IS THE
DECEASED CO-TWIN, NOT THE LIVING
TWIN.
MOSAICISM.
THE MAJORITY OF DNA IN THE BLOOD
SAMPLE FROM THE MOTHER.
AS WE LEARNED THIS IS AN
EXCEPTIONALLY SENSITIVE TEST FOR
DETECTING MATERNAL VARIATION.
THERE CAN BE EXTRA COPIES OF
SEGMENTS OF THE CHROMOSOME OF
INTEREST LIKE SECTION OF
CHROMOSOME 13 THAT MAY BE BENIGN
BUT PICKED UP AS SOMETHING HA
TRIGGERS ABNORMAL RASH REIN
MOTHER WITHOUT CLINICAL
SIGNIFICANCE.
WE ARE NOW MUCH MORE AWARE OF
WOMEN WHO MAY HAVE MOSAICISM FOR
TURNER SYNDROME OR FOR TRIPLE X
SYNDROME BUT YET DOESN'T AFFECT
FERTILITY BECAUSE BY DEFINITION
IF THEY ARE HAVING THIS H TEST
THEY ARE PREGNANT.
WE ARE AWARE OF MANY WOMEN WHO
ARE MOSAIC FOR AUTOSOMAL TRISOMY
SUCH AS TRISOMY 8, THAT DOESN'T
HAVE EFFECT ON THEIR FERTILITY,
GROWTH, DEVELOPMENT OR THEIR
INTELLIGENCE.
TRTHERE ARE A VARIETY OF MATERNAL
TREATMENTS AND CONDITIONS THAT
AFFECT QUALITY OF THE CELL FREE
DNA AND THOSE CAN TRIGGER
ABNORMALITIES IN THE
BIOINFORMATICS, THESE INCLUDE
AUTOIMMUNE DISORDERS, VITAMIN B
12 DEFICIENCY AND INTERIM COLD
STASIS OF PREGNANCY.
ONE INTERESTING THING WHEN YOU
TALK ABOUT FOR EXAMPLE SEX
CHROMOSOME ABNORMALITIES, WE ARE
AWARE OF MANY CASES WHICH Y
CHROMOSOMAL DNA IS DETECTED IN
THE MOTHERS BLOOD YET FETUS
LOOKS FEMALE ON ULTRASOUND
EXAMINATION.
TURNS OUT DNA BEING RELEASED IS
ACTUALLY FROM A PRIOR SOLID
ORGAN TRANSPLANTS SUCH AS KIDNEY
THAT WAS DONATED BY A MALE
DONOR.
ALSO FIBROIDS WHICH ARE VERY
COMMON, CAN RELEASE DNA INTO
MATERNAL CIRCULATION VIA CAUSE
OF FALSE POSITIVE RESULT SINCE
YOU MOW THIS HAS DIAGNOSIS OF
MALIGNANCY WE WILL FOCUS ON
MALIGNANCY.
YOU DON'T EXPECT MALIGNANCY WHEN
PREGNANT BECAUSE YOU ARE DEALING
WITH HEALTHY RELATIVELY YOUNG
POPULATION.
AL HOE CANCER HAS BEEN REPORTED
TO OCCUR IN ONE IN A THOUSAND TO
ONE IN 2,000 PREGNANT PEOPLE.
THE MOST COMMON TYPES OF CANCER
TO BE EXPECTED WOULD BE THOSE
ASSOCIATED WITH A RELATIVELY
YOUNG AGE AND THESE INCLUDE
BREAST CANCER, HODGKINS AND
NON-HODGKINS LYMPHOMA, CERVICAL
AND OVARIAN CANCER AND LEUKEMIA.
THE REASON WHY THIS TRIGGERS A
NON-REPORTABLE RESULT IS TUMOR
DNA IS ALSO UNDERGOING APOPTOSIS
AND SHEDDING CELL FREE DNA INTO
MATERNAL CIRCULATION.
THIS THEN CAUSES THIS
ABNORMALITY IN THE RATIO OF TEST
TO THE REFERENCE CHROMOSOMES.
YOU MAY HAVE HEARD ABOUT LIQUID
BIOPSY TEST FOR CANCER.
THE NIPT WAS NOT DESIGNED TO
DETECT CANCER, IT WAS DESIGNED
TO DETECT FETAL ANEUPLOIDY SO IT
IS REMARKABLE IT DOES IN MANY
CASES DETECT CANCER.
THE LIQUID BIOPSIES USE A
VARIETY OF APPROACHES LOOKING
FOR SPECIFIC MUTATIONS
ASSOCIATED WITH SPECIFIC CANCER,
OR SPECIFIC METHYLATION OF
GENES, OR FUSION OF GENES WITH
SOME OF THE TESTS WORK ON COPY
NUMBER ALTERATIONS THAT DISTORT
RATIO.
THAT'S WAY IT IS WORKING IN THIS
SITUATION.
NEXT SLIDE.
JUST AROUND THE SAME TIME THESE
REPORTS WERE OCCURRING OF THE
IPT TEST DOESN'T WORK, THERE'S
SO MANY POSITIVE CASES WE BECAME
AWARE OF THE FIRST REPORT OF
MATERNAL MALIGNANCY IN A WOMAN
WHO ENDED UP HAVING NIPT THREE
TIMES AND CONSISTENTLY HAD
MULTIPLE ANEUPLOIDY.
AT THE TIME SHE WAS HEALTHY
ALTHOUGH POSTPARTUM SHE
DEVELOPED PELVIC PAIN.
THE PATIENT IS SITTING HERE AND
SHE ACTUALLY WENT PUBLIC WITH
HER STORY AND GAVE AN INTERVIEW
TO MIT TECHNOLOGY REVIEW,
UNFORTUNATELY SHE HAS SINCE
PASSED AWAY.
SHE WAS PREGNANT WITH HER SON
WHO IS ON HER LAP.
SHE HAD AMNIOCENTESIS, HE WAS
NORMAL.
DIAGNOSIS WASN'T MADE UNTIL
AFTER HER DELIVERY WHEN BECAUSE
OF THE PELVIC PAIN SHE UNDERWENT
A WORK UP AND WAS SHOWN TO HAVE
WIDELY METASTATIC NEURAL
ENDOCRINE CANCER.
NEXT SLIDE PLEASE.
SINCE THAT TIME THERE HAVE BEEN
A VARIETY OF STUDIES, MOST OF
THEM HAD BEEN REROW SPECKTIVE
USING LARGE CLINICAL COMMERCIAL
DATABASES.
THE INITIAL FOCUS HAS BEEN ON
CASES WITH MULTIPLE FALSE
POSITIVE ANEUPLOIDYs DETECTED
THOUGH THERE HAVE BEEN CASES OF
CANCER WITH ONLY SINGLE
ANEUPLOIDY.
AS YOU CAN SEE IF YOU LOOK AT
THE LINE THAT SAYS NUMBER OF
CASES WITH NEOPLASTIC CONDITIONS
CONFIRM THAT LINE ADDS UP TO
WELL OVER 100 CASES OF
MALIGNANCY AND A VARIETY OF THEM
HAVE ALSO REPORTED FIBROIDS OR
LIEL MYOMAS.
THE MAJORITY HAVE BEEN SOLID
TUMORS RELEASING DNA INTO THE
CIRCULATION.
WITH THESE OVER 100 CASES MOST
WOMEN HAD BEEN HEALTHY
PRE-SYMPTOMATIC HAVE NOT BEEN
DIAGNOSED UNTIL AFTER NIPT
RESULTS.
THERE'S A RANGE OF TUMOR TYPES,
I WILL SHOW YOU NEXT SLIDE.
MAJORITY HAVE BEEN ASSOCIATED
WITH MULTIPLE CHROMOSOME
IMBALANCES WHICH ARE THE MOST
SUSPICIOUS FROM MALIGNANCY.
THE EARLIER STUDIES ESTIMATED
WHEN YOU DID SEE MULTIPLE
ANEUPLOIDIES THERE WAS A 20 TO
45% RISK OF MATERNAL CANCER BUT
MORE RECENTLY RATE OF CANCER
DETECTION IS FELT TO BE HIGHER
ALTHOUGH THERE HAS BEEN BIAS
BECAUSE THESE CASES HAVE BEEN
SELECTED FROM LARGE COMMERCIAL
OR NATIONAL DATABASES WHERE THE
OUTCOMES YOU HAVE ALREADY KNOWN.
THIS IS SHOWING YOU THE
DISTRIBUTION OF NEOPLASMS AND
PUBLISHED REPORTS, LOOK AT THE
UPPER RIGHT PART OF THE PIE
CHART, THE SKY BLUE COLOR, THOSE
ARE CASES OF LYMPHOMA.
THE GREEN DARKER GREEN, IS
BREAST CANCER, THOSE ARE THE
MOST COMMON.
THOUGH WILL IS A WIDE VARIETY OF
CANCER TYPES INCLUDING
COLORECTAL, MYELOMA, LIEL MYOWE
SARCOMA, THE MALIGNANT
TRANSMISSION FROM THE FIBROID
GASTRIC CANCER AND I WOULD SAY
IN OUR IDENTIFY STUDY WE HAVE
ALREADY HAD SEVERAL VERY UNUSUAL
CANCERS THAT HAVEN'T BEEN
PREVIOUSLY REPORTED.
APPROXIMATELY ONE IN FIVE
MATERNAL FETAL MEDICINE
SPECIALISTS HAVE ESTIMATED THAT
THEY HAVE HAD AT LEAST ONE CASE
OF CANCER IN THEIR PRACTICE.
THIS IS WHAT A REPORT COULD LOOK
LIQUEUR YOU SAW ACTUAL PATIENTS
REPORT, IN BIG LETTERS YOU SEE
IT IS NOT REPORTABLE, DOESN'T
REALLY EXPLAIN MORE THAN THAT.
A DIFFERENT TEST RESULT MIGHT
SAY TYPICAL FINDING AND LIKELY A
MATERNAL ORIGIN.
IT IS INTERESTING NOT ALL
REPORTS SAY THE SAME THING OR
EVEN INDICATE THAT THIS COULD BE
A MATERNAL CONDITION.
BUT THEY DO SAY REPEAT CELL FREE
DNA TESTING IS NOT RECOMMENDED
THOUGH THEY DO RECOMMEND GENETIC
COUNSELING, CONSULTATION WITH
MATERNAL FETAL SPECIALIST, AND
MATERNAL FETAL EVALUATIONS.
GENETIC COUNSELING IS
RECOMMENDED UNFORTUNATELY THERE
AREN'T ENOUGH COUNSELORS TO GO
AROUND FOR ALL THE ABNORMAL NIPT
CASES BUT I WANTED TO MENTION A
STUDY DONE BY MEGHAN JILES IN
THE PICTURE HERE DID A SURVEY OF
OVER 300 GENETIC COUNSELORS, A
MAJORITY WERE AWARE THAT NIPT
COULD DISCLOSE RESULTSES
SUGGESTING OF MATERNAL CANCER
THOUGH THE -- MOST DID NOT
MENTION DURING PRE-TEST
COUNSELING.
HOWEVER, 77% SAID THEY WOULD
DISCLOSE THESE RESULTS DURING
POST TEST COUNSELING.
AND THE MANAGEMENT
RECOMMENDATIONS WERE HIGH LIE
VARIABLE.
THERE WERE MIXED FEELINGS ABOUT
THE BENEFITS VERSUS THE HARM,
HOWEVER THEY ALMOST ALL SAID
INSTITUTIONAL OR NATIONAL
GUIDELINES WERE NEEDED TO INFORM
PATIENT MANAGEMENT.
IN THE UNITED STATES THERE'S
REALLY ONLY ONE PUBLICATION THAT
SUGGESTS A WAY TO MANAGE THESE
PATIENTS.
NOTICE IT DOES SAY MAGNETIC
RESONANCE IMAGE BUT PART OF THE
PROBLEM IS SO MANY STUDIES ARE
NOT COVERED BY INSURANCE BECAUSE
LACK OF PROSPECTIVE EVIDENCE TO
GUIDE MANAGEMENT.
THIS IS SUGGESTED MANAGEMENT BY
GROUP IN NORTH CAROLINA BUT IT
IS NOT BASED ON EVIDENCE SO WE
FELT THE NEED FOR EVIDENCE.
THESE ARE SOME OF THE CHALLENGES
WE FACE NOT ONLY GETTING THE
STUDY GOING BUT EVEN ONGOING
STUDY YOU WILL HEAR ABOUT IN A
MOMENT.
IF YOU LOOK IN THE UPPER LEFT
PART OF THE PIE, MANY DIFFERENT
LABORATORIES ARE OFFERING NIPT
IN THE UNITED STATES.
AND EACH ONE ANALYZES AND
REPORTS THE RESULTS DIFFERENTLY.
WE HAD DIFFICULTY WITH
CLINICIANS, NOT EVERYBODY AGREES
THESE RESULTS SHOULD BE
DISCLOSED.
IN FACT SPECIALISTS PRE-NATAL
DIAGNOSTIC SPECIALIST DEBATED
THIS LEVELLY, I MODERATED THE
DEBATE BACK IN 201, AND THERE
WAS A SIGNIFICANT AMOUNT OF
DISAGREEMENT WHETHER OR NOT THE
RESULTS SHOULD BE DISCLOSED
BECAUSE THE TEST WAS NOT
DESIGNED THE O DETECT
MALIGNANCY.
NO EVIDENCE BASED GUIDELINES.
WHEN WE HAVE TRIED TO REFER SOME
OF THESE WOMEN TO ONCOLOGISTS,
MANY ONCOLOGISTS ARE UNAWARE
MATERNAL CANCER CAN BE DETECTED
BY PRE-NATAL SCREENING.
I HAVE ALREADY MENTIONED THAT
INSURANCE COMPANIES ARE UNLIKELY
TO COVER COSTS OF MATERNAL
EVALUATION PARTICULARLY IN
HEALTHY PREGNANT WOMAN WITHOUT
SYMPTOMS.
LASTLY, THE PATIENTS ARE OFTEN
REASSURED BY LACK OF SYMPTOMS,
THEY DECLINE EVALUATION OR THEY
COULD HAVE A PARTIAL WORK UP
SUCH AS CHEST X-RAY AND IF HA IS
NORMAL THEY MAY BE FALSELY
REASSURED.
WE ARE TRYING TO DEAL WITH SOME
OF THESE CHALLENGES.
SO ED I'M GOING TO HAND THE
VIRTUAL MICROPHONE OVER TO AMY
TURRIFF WHO WILL DESCRIBE THE
IDENTIFY STUDY THAT IS BEING
PERFORMED AT THE CLINICAL
CENTER.
THANK YOU.
>> THANKS, SO MUCH.
SO THE IDENTIFY STUDY IS A
COLLABORATION AMONG NATIONAL
HUMAN GENOME RESEARCH INSTITUTE
AND NATIONAL CANCER INSTITUTE.
WE WORK VERY CLOSE WITH THE
CLINICAL CENTERS DEPARTMENT OF
RADIOLOGY AND DEPARTMENT OF
BIOETHICS.
WE ARE ENROLLING PEOPLE WHO ARE
18 YEARS AND OLDER WHO HAVE
RECEIVED ABNORMAL OR
NON-REPORTABLE NIPT RESULTS
DURING PREGNANCY.
WITH FOLLOW-UP EVALUATION THAT
SHOWS EITHER NORMAL APPEARING
FETUS ON ULTRASOUND EXAMINATION
OR NORMAL FETAL OR NEONATAL
CHROMOSOMES ON DIAGNOSTIC
TESTING.
WE CAN ENROLL PEOPLE WHILE
PREGNANT OR UP TO TWO YEARS
POSTPARTUM.
NEXT SLIDE.
ALL PARTICIPANTS COME TO NIH
CLINICAL CENTER FOR THEIR
EVALUATION NO COST FOR
PARTICIPATION WITHIN THE UNITED
STATES WE CAN ENROLL
INTERNATIONAL PARTICIPANTS, THEY
JUST MUST TRAVEL TO U.S. PORT OF
ENTRY.
THERE ARE SEVERAL OBJECTIVES FOR
THE IDENTIFY STUDY.
OUR PRIMARY OBJECTIVE IS TO
COLLECT PROSPECTIVE EVIDENCE TO
DETERMINE BEST APPROACH FOR
DIAGNOSTIC WORK UP OF PREGNANT
WOMEN WHO RECEIVED DISCORDANT
NIPT RESULTS O TO GENERATE
EVIDENCE NEEDED TO INFORM
PROFESSIONAL GUIDELINES.
WE ALSO WANT TO IDENTIFY DNA
SEQUENCING PATTERNS OR OTHER
BIOMARKERS THAT CORRELATE WITH
THE PRESENCE OF MALIGNANCY, AS
DR. BIANCHI MENTIONED
DIFFERENTIAL IS WIDE FOR THESE
CASES, WE KNOW IT IS NOT ALWAYS
GOING TO BE CANCER SO WE ARE
LOOKING TO -- THERE'S OTHER
INFORMATION THAT WE CAN USE
MOVING FORWARDS.
TO HELP PRIORITIZE THOSE CASES
LIKELY TO BE MA LEG NAN.
WE WANT TO EVALUATE RISK AND
BENEFITS OF DISCLOSING NIPT
RESULTS SUGGESTED OF MATERNAL MA
KLIGERMAN SHY AND OFFERING A
CLINICAL WORK UP DURING
PREGNANCY.
AND AS MENTIONED NIPT IS WORKING
AS A TYPE OF LIQUID BIOPSY
THOUGH IT WASN'T DESIGNED TO DO
SO SO THE FINDINGS FROM THE
STUDY CONTINUE TO CONTRIBUTE TO
BROADER AREA OF RESEARCH.
SO THIS SLIDE PROVIDES
INFORMATION WHAT TO EXPECT FROM
PARTICIPATION.
WHAT I WANT TO POINT OUT HERE IS
WE ARE COLLECTING LONGITUDINAL
PSYCHOLOGICAL IMPACT DATA FOR
PARTICIPANTS BY ASKING THEM TO
BRIEF SURVEY ENGAGE IN PHONE
INTERVIEWS WITH US.
PART OF THE CONCERNS THAT HAVE
BEEN RAISED AMONG MEDICAL
SCIENTIFIC COMMUNITY IS WHETHER
WE ARE CAUSING PSYCHOLOGICAL
HARM BY DISCLOSING THESE
UNEXPECTED SECONDARY FINDINGS
FROM NIPT.
SO WE DESIGNED THOSE INTERVIEWS
AND VARIES TO USE VOICES OF OUR
PARTICIPANTS, TO CENT TO THAT
ONGOING DIALOGUE.
-- CONTRIBUTE TO THAT DIALOGUE.
ONCE AT THE NIH CLINICAL CENTER
THEY UNDERGO A VARIETY OF
EVALUATIONS FOR MALIGNANCY
INCLUDING BLOOD WORK, FETAL
BLOOD TEST, FULL BODY MRI,
HISTORY AND PHYSICAL WITH
MEDICAL ONCOLOGIST.
WE CAN COMPLETE THE ENTIRE
EVALUATION IN A DAY AND
EVERYTHING IS SAFE TO DO DURING
PREGNANCY.
NEXT SLIDE PLEASE.
ALL RESULTS ARE SHARED WITH THE
PATIENT.
WHEN THE CLINICAL EVALUATION IS
ABNORMAL AND MALIGNANCY IS
SUSPECTED, FOLLOWING INITIAL
CONVERSATION WITH NIH ONCOLOGIST
WE WORK WITH PARTICIPANTS LOCAL
TEAM, USUALLY PRE-NATAL CARE
TEAM, TO IDENTIFY THE
APPROPRIATE PROVIDER FOR BIOPSY
AND TREATMENT IN THE
PARTICIPANTS HOMETOWN.
WHEN CLINICAL EVALUATION IS
NORMAL, WE DO STILL HAVE TO
FIGURE OUT WHAT WAS THE
BIOLOGICAL EXPLANATION FOR THAT
NON-REPORTABLE NIPT RESULT.
SO WHEN POSSIBLE WE DO EVALUATE
PLACENTA TO SEE IF ABNORMALITIES
DETECTED BY NIPT ARE COMBINED TO
PLACENTA AND IF EXPLANATION WE
ESTABLISH A PLAN FOR CLINICAL
FOLLOW-UP EVALUATION OF THE
PARTICIPANT WE ARE AWARE OF A
HANDFUL OF CASES NOW WHERE
PREGNANT WOMAN RECEIVED ABNORMAL
NIPT RESULT IN INITIAL
PREGNANCY, AND THEN THE SAME
HAPPENED A COUPLE OF YEARS LATER
WHEN SHE BECAME PREGNANT AGAIN
AND MANY CASES THE PERSON WENT
ON TO ULTIMATELY BE DIAGNOSED
WITH MALIGNANCY SO IT IS
IMPORTANT FOR US TO COLLECT
FOLLOW-UP ON ALL OUR
PARTICIPANTS, NOT ONLY WHEN
CANCER HAS BEEN DETECTED BUT
ESPECIALLY WHEN IT HAS NOT.
NEXT SLIDE PLEASE.
WHAT WAS A LITTLE BIT DIFFERENT
ABOUT THE CASE THAT WE PRESENTED
HERE TODAY IS THAT THIS
PARTICIPANT WAS ULTIMATELY
DIAGNOSED AND BEGAN CANCER
TREATMENT AFTER SHE DELIVERED
HER BABY.
IN MOST CASES WITH THE
PARTICIPANTS IN IDENTIFY STUDY
BEING DIAGNOSED WITH CANCER, IT
IS HAPPENING WHILE THEY ARE
PREGNANT.
AND THEY ARE BEGINNING TREATMENT
WHILE PREGNANT.
SO STUDIES HAVE SHOWN MANY
CANCER TREATMENT CAN BE GIVEN
SAFELY DURING PREGNANCY AND IN
MOST CASES PREGNANT WOMEN SHOULD
BE ASSESS AND TREATED IN A MANE
EQUIVALENT TO NON-PREGNANT
PEOPLE SO PREGNANCY IS NOT A
REASON TO DELAY EVALUATION OR
TREATMENT.
CANCER IS A RARE INCREASINGLY
EXPLANATION FOR NON-REPORTABLE
OR DISCORDANT NIPT RESULTS.
THOSE WITH MULTIPLE ANEUPLOIDIES
ARE MOST SO SPIES SHUTS, IT IS
NOT ALWAYS GOING TO BE CANCER,
FIBROIDS OR OTHER BETUMORS CAN
BE DETECTED BY NIPT BUT YOU
CAN'T EXCLUDE MALIGNANCY WITHOUT
HAVING DONE THE APPROPRIATE
EVALUATION.
ADDITIONAL EVIDENCE IS NEEDED TO
DETERMINE MANAGEMENT
RECOMMENDATIONS AND WHETHER
EARLY DETECTION OF OKAY CULT
MALIGNANCIES IMPROVES OUTCOMES.
PLEASE REFER CASES TO THE NIH
IDENTIFY STUDY.
SO WE WANT TO ACKNOWLEDGE
EVERYONE WHO IS INVOLVED IN THIS
STUDY.
THANK YOU ALL FOR YOUR
ATTENTION, WE WOULD BE HAPPY TO
TAKE ANY QUESTIONS.
>> THANK YOU TO ALL THE
PRESENTERS FOR THAT FASCINATING
STUDY.
WE ACTUALLY DO HAVE TWO
QUESTIONS FROM VIDEOCAST LIVE
FEEDBACK BUTTON.
I WANT TO REMIND ALL VIEWERS
THAT THEY CAN SUBMIT COMMENTS OR
QUESTIONS USING THE LIVE
FEEDBACK BUTTON ON THE VIDEOCAST
SCREEN.
THE FIRST QUESTION IS FROM
RACHEL JOHNSON, I'M GUESSING DR.
BIANCHI WHICH SEQUENCING FOR
NIPT TESTING IS LESS EXPENSIVE?
>> SO SOME OF THAT DEPENDS
WHETHER YOU ARE PAYING OUT OF
POCKET OR NOT.
IN GENERAL TARGETED SEQUENCING
IS LESS EXPENSIVE.
BUT IF YOU ARE IN A HIGH RISK
CATEGORY YOUR INSURANCE MAY BE
PAYING FOR IT AS I MENTIONED
THERE ARE MANY STATE MEDICAID
PROGRAMS THAT WILL PAY, MEDICAID
COVERS 50% PREGNANCIES
NATIONALLY SO THE STATE YOU LIVE
IN MAKES A DIFFERENCE SOSA WILL
COVER TESTING FOR HIGH RISK
PREGNANT PEOPLE WHO ARE ON
MEDICATE, IT IS A COMPLICATED
ISSUE, MANY PAYING OUT OF POCKET
ARE LOOKING FOR FETAL SEX.
I THINK IT IS FAIR TO SAY THE
WHOLE GENOME SEQUENCING APPROACH
IS MORE EXSPENDTIVE THAN THE
OTHERS.
SECOND QUESTION FROM RACHEL
JOHNSTON.
HOW ARE YOU RECRUITING WOMEN WHO
ARE RECEIVING ABNORMAL OR
NON-REPORTABLE NIPT TEST, HOW DO
YOU GET CONTACTING INFORMATION?
ARE THEY BEING REFERRED?
I GUESS THAT IS THE GIST ANOTHER
QUESTION.
>> I WILL SAY COUPLE OF THINGS
THEN HAND TO AMY FIRST POINT OF
CONTACT.
WE ARE DOING OUTREACH SPEAKING
ABOUT THE PROJECT AT
PROFESSIONAL SOCIETY MEETINGS
AND AT CME COURSES, GIVEN OTHER
GRAND ROUNDS.
SO WE HOPE PEOPLE ARE WARE OF IT
AND USING GENETIC COUNSELING
LIST SERVE TO ADVERTISE THE
STUDY OTHERWISE IT IS PRETTY
MUCH WORD OF MOUTH, THEN WE
RECOMMEND THEY CONTACT AMY SO
MAYBE AMY YOU CAN DESCRIBE WHAT
HAPPENS AFTER THAT.
>> SURE.
MOST RELATES COME THROUGH A
GENETIC COUNSELOR OR THE
PATIENT'S PRE-NATAL PROVIDER
WHETHER MATERNAL FETAL MEDICINE
SPECIALIST, MIDWIFE, OB, THE
PERSON WHO'S THIS NON-REPORTABLE
RESULT LANDED ON THEIR DESK.
THERE ARE COMMERCIAL
LABORATORIES HERE IN THE UNITED
STATES OFFERED NIPT.
ALL OF THEM ARE AWARE THAT WE
ARE DOING THIS STUDY.
USUALLY THERE IS A LOT OF
CONVERSATION THAT HAPPENS
BETWEEN NIPT LABORATORY, AND THE
ORDER AND CLINICIAN WHEN THESE
CASES COME UP.
MOST PROVIDERS HAVEN'T SEEN THIS
BEFORE, THIS MIGHT BE THE FIRST
TIME THEY HAVE RECEIVED THIS
NON-REPORTABLE RESULT.
SO THE LABS TRY TO OFFER SOME
GUIDANCE TO WHAT SHOULD BE
CONSIDERED AND WHAT MIGHT BE
APPROPRIATE FOLLOW-UP FOR THE
PATIENT.
BECAUSE WE HAVE THIS ONGOING
STUDY I THINK SOMETIMES
COMMERCIAL LABORATORIES DO
ACTUALLY MAKE SURE THAT THIS
ORDERING CLINICIAN IS AWARE THAT
THIS WOULD BE AN OPTION TO
CONSIDER FOR THE PARTICIPANTS OR
PATIENT.
>> THANK YOU.
THE NEXT QUESTION IS FROM
PATRICIA WILLIAMS.
REGARDING MRI HOW LONG DOES
WHOLE BODY MRI TAKE TO PERFORM
AND IS IT DONE SINGLE SESSION?
AND IS THERE A SPECIFIC TYPE OF
MRI MACHINE THAT IS PREFERRED
FOR PREGNANT WOMEN OR IS THIS
JUST A ROUTINE MRI?
>> WHAT WE DO AT NIH IS NOT A
ROUTINE MRI YOU CAN GET
ANYWHERE.
THE WAY WE DO IT, THE WAY IT'S
DONE, WE USE A POWER MAGNET AS I
MENTIONED BECAUSE WE WANT TO BE
EXTREMELY SAFE WITH THE FETUS.
WE USE A 1.5 TIER SCANNER.
THIS IS -- EVERYTHING IS DONE IN
ONE SESSION.
SO DEPENDING ON WHAT IS
PROTOCOL, WHAT PROTOCOL WE ARE
DOING STUDY FOR, THIS IS NOT THE
ONLY TIME WE USE WHOLE BODY MRI.
SOMETIMES WE HAVE TO GIVE
CONTRAST, SOMETIMES IN OTHER
PROTOCOLS NOT IDENTIFY STUDY,
WHOLE BODY MRI MAY TAKE LONGER.
FOR IDENTIFY STUDY PARTICIPANTS
IT USUALLY TAKES 45 MINUTES TO
AN HOUR TO BE IN THE SCANNER.
>> MAY I ADD, WE HAVE HAD THE
SITUATION SINCE STUDY STARTED
PRIOR TO BEGINNING OF THE
PANDEMIC, WE HAD SEVERAL
PARTICIPANTS WHO WANTED TO COME
BUT WERE UNARABLE TO TRAVEL
EITHER BECAUSE THEY COULDN'T
CROSS THE CANADIAN BORDER OR
DIDN'T WANT TO FLY ACROSS THE
COUNTRY.
SO THEY DID HAVE MRI BUT THEY
COULDN'T HAVE A WHOLE BODY MRI.
SO THEY ENDED UP HAVING MULTIPLE
MRIs, SOMETIMES ON DIFFERENT
DAYS JUST TO COVER THE ENTIRE
BODY.
THAT IS ONE OF THE GREAT
ADVANTAGES OF THIS STUDY, IS IT
CAN ALL BE DONE AT ONCE IN A
RELATIVELY LIMITED PERIOD OF
TIME.
IT DOESN'T COST ANYTHING WHICH
IS A MAIN EVENT.
>> ANOTHER QUESTION FROM -- IS
THERE ANY WORK UNDERWAY TO
ORIGINAL NIPT SEQUENCING RESULTS
TO REFINE ASSESSMENT OF MOST
LIKELY CAUSE OF THE PERTURBATION
THAT IS TO SAY WHETHER MATERNAL
VERSUS FETAL, FIBROMAS OR VERSUS
MALIGNANCIES.
RELATED QUESTION TO THAT, IS
COULD THERE BE A FUTURE FINITE
ASSAY AS ROUTINE CANCER
SCREENING IN THE GENERAL
POPULATION?
PART OF OUR STUDY IS TO USE NOT
ONLY THE GENOME SEQUENCING BUT
TO LOOK FOR DEEPLY FOR EXAMPLE
IN TISSUE OF ORIGIN AND ALSO
LOOKING AT OTHER WAYS THAT
TISSUE OF ORIGIN CAN BE DETECTED
IN SAMPLES SUCH AS METHYLATION
USING RESEARCH BLOOD SAMPLES.
NOT EVERYBODY WILL HAVE ACCESS
TO AN MRI SO IT WOULD BE GREAT
IF ULTIMATELY YOU COULD AT LEAST
DETERMINE SOMEONE IS MUCH MORE
LIKELY TO HAVE CANCER WHEN
SIMPLY A BLOOD TEST.
WE WILL HAVE ALL SEQUENCES
AVAILABLE, WE HAVE THE RESEARCH
DATA AVAILABLE TO DO DEEPER
DIVES AND DEEPER ANALYSIS.
THAT IS ON THE ORIGINAL WHOLE
GENOME SEQUENCE.
I DON'T THINK WE MENTION THAT
EACH OF THE PARTICIPANTS WILL
HAVE HAD INITIAL NIPT BY ONE OF
SEVERAL COMPANIES.
ONCE THEY ENTER THE STUDY WE
REPEAT THE NIPT USING A SINGLE
LABORATORY.
SO WE CAN COMPARE EVERYONE'S
RESULTS TO THE OTHER
PARTICIPANTS.
QUESTION OF WHETHER YOU WOULD
USE NIPT APPROACH, THE WAY THE
BIOINFORMATICS ALGORITHMS ARE
BEING USED TO DETECT
ABNORMALITIES IN RATIOS, THERE
ARE GROUPS DOING THAT, WHETHER
OR NOT THAT'S THE MOST COST
EFFECTIVE AND EFFICIENT AND
ACCURATE WAY OF SCREENING FOR
CANCER I CAN'T ANSWER THAT BUT
CERTAINLY THE CONNECTION SAY
BETWEEN ALUMINA SEQUENCING
APPROACH AND THE GRAIL APPROACH
WHICH IS NOW SUPPOSED TO BE
TAKEN OVER BY ALUMINA, THAT
THERE IS THAT CONNECTION THERE
SO THEY ARE AWARE OF THE FACT
THAT THE INITIAL ANEUPLOIDY
SCREENING APPROACH MIGHT ALSO BE
USED IN A CANCER CONTEXT.
BUT AGAIN, THAT MAY NOT BE THE
CHEAPEST WAY TO DO SCREENING.
THE LIQUID BIOPSY APPROACH IS
REALLY BEING RECOMMENDED AS
SCREEN FOR EVERYBODY WHO MIGHT
BE AT RISK FOR CANCER SO IT IS
PART OF YOUR ANNUAL PHYSICAL YOU
COULD HAVE A BLOOD TEST INSTEAD
OF A COLONOSCOPY FOR EXAMPLE.
>> THIS IS KIND OF A FOLLOW-UP
ON THAT.
FOR THE INSTANCES OF POSITIVE
NIPT THAT YOU KNOW OF, WHAT
PROPORTION OF THESE CASES HAVE
NEGATIVE MRI OR PET FINDINGS AND
DOES THIS DIFFER DEPENDENT ON
MALIGNANCY ORIGIN OR TYPE?
I GUESS THIS IS ONE OF THE
QUESTIONS YOUR STUDY WILL BE
ANSWERING.
>> YEAH.
I DON'T THINK WE ARE READY TO
DISCLOSE OUR RESULTS OTHER THAN
TO SAY EVEN FROM THE VERY
BEGINNING WHEN OUR VERY FIRST
PARTICIPANT WAS SHOWN THAT
CANCER, WE ARE DETECTING CANCER
AT A VERY HIGH RATE.
WHAT IS SURPRISING THOUGH IS THE
WIDE VARIETY OF CANCERS AND
CANCERS THAT EVEN PATHOLOGISTS
DON'T AGREE ON THE UNDERLYING
DIAGNOSIS.
WHEN THEY HAVE THE CANCER IN
FRONT OF THEM UNDER THE
MICROSCOPE.
AGAIN, I WANT TO EMPHASIZE THAT
OUR STUDIES ARE PROSPECTIVE SO
WE ARE TAKING A REAL LIKE
APPROACH, WHAT DO YOU DO IN THIS
SITUATION AND THEN HAVING EACH
PARTICIPANT UNDERGO THE SAME
PROTOCOL SO WE CAN EFFECTIVELY
GIVE ACCURATE ESTIMATE OF WHAT
IS THE RISK.
TAKING ALL WOMEN AND NOT BIASING
IT WITH SOME SORT OF
RETROSPECTIVE KNOWLEDGE.
I WOULD SAY THAT AT LEAST OF THE
WOMEN WHO HAVE COME TO THE
CLINICAL CENTER, THERE IS A VERY
HIGH RISK OF CANCER.
>> SO THIS QUESTION ACTUALLY
JUST TOUCHES ON WHAT YOU JUST
SAID, DR. BIANCHI.
IT SAYS DR. BIANCHI MENTIONED A
BIAS MAY EXIST IN THE POSITIVITY
RATE OF CANCER DETECTED DRAWING
FROM AVAILABLE DATA SETS.
CAN YOU EXPAND ON POTENTIAL
BIAS?
THANK YOU.
>> YES.
SO AGAIN, MUCH OF THE LITERATURE
COMES FROM THE NATIONAL
DATABASES OR THESE CLINICAL
TESTING LABORATORY DATABASES.
WHERE AT LEAST IN THE NATIONAL
REPORTS COMING FROM BELGIUM
AUSTRALIA AND NETHERLANDS, THEY
-- WHAT THEY ARE DOING THERE IS
THEY KNOW THE WOMAN HAS CANCER
AND THEN THEY ARE GOING BACK TO
LOOK AT WHAT DID THE
BIOINFORMATICS RESULTS SHOW AND
NOW THAT THEY KNOW WHAT IT COULD
LOOK LIKE THEY ARE ABLE TO DO A
BETTER JOB PREDICTING
PROSPECTIVELY WHO MIGHT HAVE
CANCER BUT THE LITERATURE WE
SHOWED IN THOSE SLIDES INCLUDING
OUR OWN REPORT FROM TUFTS BACK
IN 2015, WERE BIASED WITH
KNOWLEDGE THESE WOMEN DID HAVE
CANCER.
I SHOULD ALSO SAY THERE ARE MANY
GROUPS IN EUROPE THAT ARE USING
FREELY AVAILABLE SOFTWARE THAT
AUTOMATICALLY DISPLAYS ALL
CHROMOSOMES.
ONE OF THE DIFFICULTIES MANY THE
UNITED STATES IS THAT EACH
COMMERCIAL LABORATORY USES A
DIFFERENT BIOINFORMATICS
APPROACH.
SO THEY INTERPRET THE RESULTS
DIFFERENTLY, THEY MASK THE
RESULTS DIFFERENTLY, AND YOU ARE
NOT OPENING UP A WHOLE GENOME
SEQUENCING RESULTS TO SEE WHAT
IS GOING ON WITH SOME OF THE
LABORATORIES IN EUROPE THESE
NATIONAL LABORATORIES THEY SEE
RIGHT AWAY IF THERE ARE
ABNORMALITIES IN MULTIPLE
CHROMOSOMES.
WE SHOULD POINT OUT THAT WHEN
YOU GET A RESULT OF MONOSOMY FOR
CHROMOSOME 1 AND TRISOMY FOR
CHROMOSOME 2 AS WE HAD IN THIS
CASE THAT'S NOT CONSISTENT WITH
NORMAL FETAL DEVELOPMENT.
AND WHEN THIS WOMAN PRESENTED
EVEN LATE -- EARLY SECOND
TRIMESTER, THE FETUS WAS
DEVELOPING NORMALLY AT THAT
POINT, SO U YOU DO HAVE THIS
DISCREPANCY THERE THAT WE NOW
HAVE A MUCH HIGHER CONCERN THAT
IT IS COMING FROM THE MOTHER,
THOUGH IT COULD BE -- YOU CAN
GET MULTIPLE ANEUPLOIDIES WITH
CONFINED MOW SAFE HARBORRISM.
>> OKAY.
I WILL JUST REPEAT WITH WHAT WAS
SAID, BOTH MYSELF AND FROM ONE
OF THE COMMENTATORS.
THANK YOU FOR THIS INTERESTING
INFORMATIVE PRESENTATION.
IT WAS REALLY A DELIGHT HAVING
YOU ALL PRESENT TODAY.
>> THANK YOU FOR HAVING US.