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.