OUR FIRST SPEAKER TODAY IS MUKESH VERMA. I HAVE KNOWN HIM FOR ALMOST 30 YEARS. HE AND I BOTH USED TO WORK AT GEORGE WASHINGTON UNIVERSITY. THEN HE CAME TO THE DIVISION OF CANCER PREVENTION AND SUBSEQUENTLY HE JOINED DCCPS IN 2004 AS A PROGRAM DIRECTOR. HE BECAME THEN ACTING CHIEF OF THE ANALYTIC EPIDEMIOLOGY RESEARCH BRANCH AND THEN IN 2007, HE BECAME BRANCH CHIEF OF THE METHODS AND TECHNOLOGIES BRANCH. SO HE IS GOING TO TALK TO US TODAY ABOUT EPIGENETICS. IT'S NOT JUST GENE MUTATIONS. GENE SILENCING IS VERY IMPORTANT TOO. >> THANK YOU. SO TODAY I WILL BE TALKING ABOUT EPIGENETICS. THIS IS A DIFFERENT WAY OF GENE REVELATION. SINCE I'M FROM THE GENOMICS PROGRAM, I WILL COVER HOW THIS IS IMPORTANT AND HOW WE CAN UTILIZE THAT TO IDENTIFY PEOPLE WHO ARE AT HIGH RISK OF DEVELOPING CANCER AS WELL AS HOW EPIGENETIC APPROACHES CAN BE NUDES CLINIC. FEW HAVE BEEN APPROVED BY FDA AND WHAT CLINICAL TRIALS ARE BEING DONE. AND WHAT IS THE MECHANISM BEHIND EPIGENETICS? ALL OF THOSE THINGS I'M GOING TO COVER IN THE TALK. SO SINCE I'M FROM THE CANCER INSTITUTE AND WE WORK ON EPIDEMIOLOGY AND GENOMICS -- CAN YOU HEAR WELL? OKAY. SO CANCER, AS YOU KNOW, THIS IS A SERIOUS DISEASE IN WHICH PROSTATE CANCER AND BREAST CANCER IN MEN AND WOMEN, THEY ARE THE NUMBER 1 KILLERS. 1.6 MILLION MEN AND 2.2 MILLION JUST WITH THIS CANCER, THEY ARE AFFECTED. AND THIS NUMBER IS GROWING. ALTHOUGH WE HAVE SUCCEEDED A LITTLE BIT BY SCREENING AND OTHER METHODS, SURVIVAL AND QUALITY OF LIFE IS BETTER. IN 2010 IT WAS ESTIMATED THAT 13.6 CANCER SURVIVORS BUT IN 2022 WE EXPECT THE NUMBER WILL INCREASE TO 18 MILLION. HERE THE DISTRIBUTION OF INCIDENTS LIKE NEW CASES AND HOW MUCH THEY SURVIVE IN MEN AND WOMEN, THEY ARE SHOWN FOR DIFFERENCE ESPECIALLY FOR COLON CANCER OR BREAST CANCER, SCREENING HAS BEEN VERY USEFUL AS WELL AS EARLY DETECTION MARKERS HAVE BEEN USEFUL IN DIFFERENT CANCERS. CANCER RESEARCH IS A DISEASE FOR MAJOR CANCERS LIKE BREAST, CERVIX, COLON, PROSTATE AND LUNG, IT TAKES MANY YEARS TO DEVELOP. THOSE ARE STAGES WHICH COME AT DIFFERENT TIMES, THOSE ARE DEFINED. SO THE IDEA IS IF WE CAN CHARACTERIZE OR FOCUS MORE ON EARLY STAGES, THEN WE HAVE MORE OPTION OF CHANCE FOR DOING CHEMO PREVENTION OR THERAPY OR OTHER ASPECTS WE CAN DO. USUALLY WHEN BIOLOGY WAS DEVELOPED AND GENETICS WAS DEVELOPED FIRST. SO IN THAT, SOME MUTATIONS IN SPECIFIC GENES -- THIS IS A MODEL OF COLON CANCER. THOSE WERE IDENTIFIED. SOME WERE FROM INITIATION AND THEN PREMALIGNANT. AND THOSE KINDS OF INFORMATION WERE USEFUL. BASED ON THAT AND BASED ON THE AGE OTHER AND TIME DIFFERENT -- YOU WILL SEE FOR BREAST CANCER, ATYPICAL HYPERPLASIA AND ALL THAT AND FOR COLON CANCER ALSO. SO IN GENETIC TERMS AND WILL HISTOLOGICAL TERMS, CANCER WAS CHARACTERIZED VERY MUCH. THEN CAME THE TECHNOLOGIY WHEN SEQUENCING WAS MORE POPULAR. IT WAS CALLED A SNP CHARACTERIZATION AND THEN GENOME-WIDE ASSOCIATION STUDIES. WHAT HAPPENS IS THOSE ARE SMALL CHANGES IN DNA SEQUENCE WHETHER WE CAN LINK TO THE CHROMOSOME LOCATION OR NOT. SO IN 2005, BASICALLY FIRST GWAS WAS DONE AND THESE ARE DIFFERENT CHROMOSOMES. AND AS TIME PASSES BY, FOR DIFFERENT CHROMOSOMES, DIFFERENT GENES WERE LOCALIZED WHICH WERE ASSOCIATED WITH NOT ONLY CAPSER BUT OTHERS ALSO. SO, BY THE TIME 2008 OR 9 FOR MOST OF THE CHROMOSOME LOCATION, BY GWAS THEY WERE IDENTIFIED. SO THIS IS THE SITUATION. NOW BECAUSE OF THAT, WE WANTED TO UTILIZE THAT WHAT INFORMATION IN GENETICS IS THERE, HOW WE CAN USE THAT FOR EPIGENETICS. SO IF YOU SEE IN GENETICS THE WAY THEY HAVE IDENTIFIED FOR DIFFERENT KINDS OF CANCERS AND DIFFERENT LOCATIONS, HOW MANY ARE THERE, WHERE THEY ARE, SIMILAR THING WE WANT TO DO IN EPIGENETICS. IN CANCER MODEL, BASICALLY 12 PATHWAYS WHICH PROPOSED, THEY ARE THE MAJOR PATHWAYS SO THAT HAS ALSO BEEN CHARACTERIZED. NOW COMES EPIGENETICS. SO IN GENETICS YOU KNOW THEY ARE HER EDITED. BUT WITHOUT CHANGING THE GENE STRUCTURE. GENE EXPRESSION CHANGES THAT IS CALLED EPIGENETICS. SO WE KNOW ABOUT GENETIC CORD AND EPIGENETICS WE HAVE TWO CODE, METHYLATION CODE AND HIS STONE CODE AND I WILL DISCUSS MORE ABOUT THOSE. SO GENETICS WILL TELL WHAT YOU ARE CAPABLE OF BUT EPIGENETICS WILL CONTROL WHEN SOMETHING YOU SHOULD BE DOING AND WHEN YOU SHOULD STOP THAT. SO THAT KIND OF REVELATION IS CALLED EPIGENETICS. AND BY TERMINOLOGY ALSO, EPIMEANS ABLE. GENETICS SO WHAT IS ABLE GENETICS? TIME TO TIME YOU SEEN IN POPULAR MAGAZINES SOME ARTICLES THAT YOUR DNA IS NOT YOUR DESTINY BECAUSE IT WAS FOUND THAT BY CHANGING BEHAVIOR, LIFESTYLE OTHER AND THINGS, YOU CAN CHANGE EXPRESSION OF GENES. AND IN TERMS YOU CAN AVOID A DISEASE. TO DISTINGUISH GENETICS AND EPIGENETICS, SOME EXPERIMENTS WERE DONE IN MONOZYGOTIC TWINS WHERE GENETIC MAKEUP WAS EXACTLY THE SAME BUT IN THAT WHAT WAS FOUND THAT A LOT OF DISCORDANCE WAS THERE. EITHER IN CARDIOVASCULAR DISEASES OR OTHER DISEASES AND THAT IS HOW EPIGENETICS CAME. AND IN THAT THEY FOUND THAT WITHOUT DNA STRUCTURE CHANGE, SOME CHANGES WERE THERE. THAT THE GAVE US THE IDEA OF EPIGENETICS PREDISPOSITION. LIKE IF YOU SEE EPIGENETICS CHANGES, THAT PERSON IS AT HIGH RISK. PHARMACOGENOMICS LIKE BASED ON GENETIC BACKGROUND, PEOPLE CAN TREAT, SAME WAY EPIGENETIC BACKGROUND ALSO, THAT IS GIVEN RISE TO PHARMACOEPIGENOMICS FOR PERSONALIZED MEDICINE. AND THIS YEAR ALSO WHEN ARTICLE CAME THAT CANCER EPIGENETICS IN THE DRIVER'S SEAT BECAUSE SUCH CHANGES PEOPLE ARE IDENTIFYING WHICH ARE THE STARTING POINT. WHICH STAGE THERE ARE NO MUTATIONS THE SNPS ARE IN ANY KIND OF CHANGES BUT GRADUALLY, METHYLATION CHANGES OR OTHER CHANGES, EM GENETIC CHANGES, THEY ARISE. TO GIVE YOU BACKGROUND ABOUT CHROMATIN, IT IS MADE UP OF HIS STONES. H1 IS A LINKER AND THESE ARE 146 BASE PAIR LONG AND THEY ARE TO NEUTRALIZE THE CHARGE OF DNA AND TO DISTRIBUTE CHROMATIN. IN PROMOTOR REGION, CGCG SEQUENCES ARE VERY COMMON. NORMALLY THIS IS THERE BUT SOMETIMES ESPECIALLY IN DISEASE INITIATION. CYTOGAS METHYLATED AT 5 PRIME SITE AND THAT CAN CAUSE GENE SUPPRESSION AND IT IS OBSERVED IN TUMOR SUPPRESSOR GENE. AT THE SAME TIME, SOME GENES ARE SUCH THAT CG SEQUENCES ARE ALREADY METHYLATED AND THEY GET HYPOMETHYLATED AND THAT WAS OBSERVED IN ONCOGENES. SO FOR DIFFERENT GENES, DIFFERENT KIND OF REGULATION IS THERE. IN EPIGENETIC REGULATION, MOSTLY COMPONENTS ARE EITHER METHYLATION, WHICH IS DONE BY DNA METHYLTRANSFERASE GENES, 13AB DIFFERENCE ARE THERE. SOME ARE FOR INITIATION METHYLATION, SOME ARE FOR MAINTENANCE. HIS STONES ARE THERE WHICH GET MODIFIED BY ACETYLATION, PHOSPHORYLATION OR OTHER KINDS. THEN COMES NON CODING RNA LIKE MICRORNA AND OTHERS. THEY ALSO REGULATE GENE EXPRESSION. YOU WILL HEAR A FEW TERMS I WILL INTRODUCE LIKE ARE SHORES AND SHELLS. LIKE THE CG SEQUENCES IF IN 2-4KB, 60% SEQUENCES ARE THERE THEY ARE CALLED IRELAND. BUT IF THOSE SEQUENCES CPG SEQUENCES ARE LESS THAN TWO KB, THEN THESE ARE CALLED SHORES AND 2-4KB, THEY ARE CALLED SHELLS AND OTHER IS CALLED OPEN SEA. THESE ARE THE TERMS FROM TIME TO TIME THEY ARE COMING. SO THE COMPONENT OF EPIGENOMICS, METHYLATION REGULATION IS THE MAIN ONE. THEN METHYLTRANSFERASE GENES AND THEN HISTONE MODIFICATIONS COMPARED CHROMATIN VERSUS RELAXED CHROMATIN. THAT IS DONE BY DIFFERENT MODIFICATION, ACETYLATION, BIOTINYLATION, METHYLATION, PHOSPHORYLATION AND UBIQUITINATION. AND THEN microRNA AS WELL AND THEN SOME NON HISTONE PROTEINS AS WELL ARE CHROMATIN FOLDING PROTEINS. THEY ARE THERE. FOR HISTONES, DIFFERENT KINDS OF ENZYMES OF PROTEINS ARE THERE THAT HAS BEEN CHARACTERIZED. NOW SOME SEQUENCES ARE CALLED REPEAT SEQUENCE. THEY ARE VERY MUCH INVOLVED IN GENOME INSTABILITY. THEY ARE IMPORTANT FROM THAT POINT OF VIEW. GENOME AND EPIGENOME WHEN WE CHARACTERIZE GENOME IN ALL CELLS THE SAME KIND OF DNA THERE WHETHER MUTATE FROM BLOOD OR LUNG OR COLON. YOU HAVE TO SEQUENCE ONLY ONCE. ANY TIME YOU ARE DOING LONGITUDINALLY MANY SAMPLES YOU HAVE TO TAKE, THAT CHANGES AND WOULD COORDINATION. AND IN MONOWE HAVE GOING TOIT 26 MANY STUDIES HAVE BEEN DONE -- MONOZYGOTIC TWINS. OTHER GENETIC COMPONENTS DOMINATE WHILE IN CANCER AND A FEW OTHER DISEASES, EPIGENETIC INFLUENZA IS MORE. LIKE GENETICS, BY DIET OR LIFESTYLE OR ENVIRONMENT, EPIGENETIC CHANGES HAPPEN. NOW MORE IMPORTANT IS THAT WHEN EPIGENETICS CAN HAPPEN, SO USUALLY THE ORDER OF WHICH CAN HAPPEN THAT IS QUITE EARLY BEFORE BIRTH OR AFTER BIRTH. YOU CAN SEE BASED ON THAT WAY OF HOW MANY ORDER OF DEFECTS CAN HAPPEN EARLY AND LATER ON, THEY ARE LESS AND IN THIS REGARD YOU SEE, THAT MOSTLY AT INITIAL STAGES MATERNAL FACTORS OR ENVIRONMENTAL FACTORS GOES TOGETHER INFLUENCE FOR INITIATION OF DISEASE. LATER ON IT BECOMES MOSTLY LIFESTYLE AND DIET. SO THAT IS HOW THEY ARE DEFINED. AND AT THE SAME TIME, DIFFERENT STAGES OF LIFE CYCLE, DIFFERENT KIND OF BIOSPECIMEN OR SAMPLES CAN BE COLLECTED WHICH CAN BE CHARACTERIZED FOR EPIGENETICS. IF YOU THINK ABOUT SOME PREGNANT WOMEN THEN IF THAT PERSON IS SMOKING, THEN MOTHER IS EFFECTED AND FETUS AND THEN REPRODUCTIVE CELLS. SO EVEN 3 GENERATIONS CAN BE AFFECTED. AND EPIGENETIC CHANGES ARE MOST SUSCEPTIBLE THAN GENETIC CHANGES. SO AT NIH, OR NCI, EMPHASIZE ON EARLY-LIFE EXPOSURE AND HOW WE CAN UTILIZE THAT. ANDED ANOTHER POINT I WANT TO MENTION ABOUT RISK ASSESSMENT OR IDENTIFYING HIGH RISK POPULATION. IF YOU WANT TO DO THAT THEN FEW THINGS ARE ESSENTIAL LIKE WE WANT TO HAVE CERTAIN POPULATIONS WHERE DISEASE HAVE NOT DEVELOPED BUT YOU HAVE ALL INFORMATION ABOUT EXPOSURE, WHETHER CHEMICAL, RADIATION, INFECTIOUS AGENTS, TOXIC SUBSTANCE, FAMILY HISTORY, DIET AND MEDICATION. AND THESE BIOSPECIMENS SHOULD BE COLLECTED NON-INVASIVELY. THEN WE NEED FOLLOW-UP LIKE SEVERAL TIMES YOU HAVE TO TAKE. WHAT ARE THE CHALLENGES OR DRAWBACKS IN THESE KINDS OF EXPERIMENTS OR STUDY DESIGN? THESE ARE EXPENSIVE AND DATA SHARING MANY TIMES PEOPLE DON'T DO BUT THEY SHOULD DO. BUT ADVANTAGES, THESE ARE ESSENTIAL IF WE WANT TO IDENTIFY THE FACTORS CONTRIBUTING TO A DISEASE SO YOU CAN DEVELOP SOME THERAPEUTIC APPROACHES. SO IN OUR PROGRAM, WE HAVE SAMPLES FROM DIFFERENT POPULATIONS WHETHER AFRICAN-AMERICAN, ASIAN, LATIN-AMERICAN OR HAWAIIAN. THE REASON IS WHEN A DRUG IS DEVELOPED, ALL PEOPLE FROM DIFFERENT RACIAL AND ETHNIC GROUPS, THEY DON'T RESPOND THE SAME WAY. WE WANT TO GET INVOLVED WITH OTHER POPULATIONS ALSO. SO THESE ARE THE COUNTRIES FROM WHICH WE COLLECT SAMPLES, WE SUPPORT THEM AND THEY STORE THAT AND WE HAVE 2.3 MILLION SUBJECTS OR SPECIMEN AND THOSE COHORTS WHERE DISEASE HAVE NOT DEVELOPED BUT WE HAVE ACCESS TO THOSE, SEVERAL OF THAT PROGRAM SUPPORTS AND SOME HAVE BEEN GOING ON SINCE EARLY 70s LIKE PHYSICIAN HEALTH STUDIES. SO TOTAL 64 COHORTS OF PROGRAM SUPPORT AND MEMBERSHIP SHOULD BE THAT MINIMUM 10,000 SAMPLES THEY SHOULD SUPPLY. AND THAT WHY WE GET GEE WAS STUDIES DONE AND THEN THE SAME SAMPLE OF PEOPLE WE WERE USING IN FUTTOWER COLLECT SAMPLES SO BY EPIGENETICS WE CAN ANALYZE. SO FROM TIME TO TIME TO PROMOTE THIS PROGRAM, WE ARRIVE IN DIFFERENT JOURNALS AND ARTICLES& LIKE EARLY-LIFE EXPOSURE TO INFECTIOUS AGENTS AND LATER CANS IR DEVELOPMENT THAT I DID BEFORE SOMETIME. AND WILL AT NIH LEVEL SOME MONIES IS CONGRESSIONALLY MANDATED. SO THIS PROGRAM IN HALF YEAR WE INITIATED IS CALLED ECHO. OR ENVIRONMENT AND INFLUENCES ON CHILD HEALTH OUTCOME. BEFORE PREGNANCY, THOSE MOTHERS ARE ENROLLED AND SOME ARE ALREADY HAVING A SMALL CHILDREN OR BABIES. SO IN THAT ABOUT 165 MILLION DOLLAR PER YEAR WILL BE SPENT ON FOR SEVEN YEARS COMMITTED AND THEN IN THIS PROGRAM, WE HAVE DATA ANALYSIS CENTER OR THAT CENTER WHICH CAN DO THE ANALYSIS OR GENETIC CODE OR COORDINATION CENTER. SO THAT IS HOW IT IS DONE. AND DIFFERENT LIFE STAGES ARE THERE WHERE SAMPLES WILL BE COLLECTED LIKE PRECONCEPTUAL, ANYTHING PRIOR TO LABEL, PERINATAL, INFANCY, EARLY CHILDHOOD, MIDDLE CHILDHOOD AND ADOLESCENCE. AND FOR SEVEN YEARS IT WILL BE FOLLOWED AND CHANCES ARE THAT FOR NEXT SEVEN YEARS ALSO IT WILL BE FOLLOWED. SO, WHEN EARLY IN LIFE YOU GET EXPOSED AND WHICH DISEASE YOU DEVELOP, THEY WILL FIND OUT. ONCE YOU FIND OUT, THEN YOU CAN GO BACK TO THE SAMPLES TO SEE WHETHER ANY MOLECULAR CHANGES YOU CAN SEE WHICH YOU CAN CORRELATE WITH THE DISEASE. EPIGENETICS HAS BEEN ASSOCIATED WITH BEHAVIOR ALSO AND SOME PAPERS YOU WILL SEE LIKE EPIGENOME WIDE ASSOCIATION STUDIES WHICH CORRELATE WITH AGGRESSIVE BEHAVIOR. MANY THINGS WITH GENETICS WE COULD NOT UNDERSTANDED WITH EPIGENETICS WE CAN DO. THIS WAS FOR BIOPSYCHOSOCIAL PATHWAYS IN EPIGENETICS REGULATION. AND MANY TIMES WE HEAR ABOUT HEALTH DISPARITIES. WHICH IS IN SOCIAL, ECONOMIC BACKGROUND, THOSE PEOPLE WHO DO NOT HAVE GOOD RESOURCES IN THOSE DISEASE ARE DEVELOPING. SO IN THAT ALSO WHAT WE ARE PROPOSING THAT EPIGENOMIC PROFILING THEY SHOULD DO. SO THAT KIND OF PROGRAM ALSO WE ARE PROMOTING. AND IN THIS WE HAVE SHOWN LIKE GENOME-WIDE ASSOCIATION STUDIES YOU DO SIMILARLY, THOSE COMPONENTS LIKE METHYLATION PROFILING, HISTONE PROFILING OR CHROMATIN ACCESSIBILITY, YOU DO BUT IF YOU PUT THESE TOGETHER THEN YOU CAN GET BETTER RESULTS AND BETTER SENSITIVITY TO THOSE BIOMARKERS. AND EPIGENETICS IS ALSO AFFECTED BY RADIATION AND INFECTIOUS AND TOXIC SUBSTANCES ULTIMATELY THAT INTERMEDIATE PHENOTYPE COMES AND DISEASE DEVELOP. THIS ALSO WE FACE CHALLENGES BUT WE HAVE PROPOSED ALSO CERTAIN KIND OF SOLUTIONS FOR EXAMPLE, SAMPLE COLLECTION, WHAT KIND OF SAMPLES SHOULD WE HAVE, WHAT STUDY DESIGN IS THERE? WHAT TECHNOLOGY WE HAVE WHETHER HIGH-THROUGHPUT IS THERE OR NOT? AND I'M GOING TO TELL YOU ALSO ABOUT THE TECHNOLOGY HOW THIS EPIGENETICS IS DONE. AND IN AN ENVIRONMENT, THOSE AGENTS WHICH PREVIOUSLY USED TO BE FOR MUTATION ONLY NOW ARSENIC, CADMIUM, CHROMIUM AND NICKEL, AND ALL DO EPIGENETIC CHANGES IN DIFFERENT KINDS OF CANCERS. SO THAT WAY MORE AND MORE EVIDENCES ARE COMING. AND ONE PAPER CAME ABOUT CROSS GENERATION EFFECTS OF ALCOHOL DEPENDENCE. IN THAT ALSO METHYLATION WAS THE REGULATOR MECHANISM. THE WAY TOX COGENOMICS IS DONE BY GENOMIC CHANGES OUT THERE, NOW PEOPLE ARE STUDYING THAT BEFORE GENOMICS EPIGENOMICS ALSO ARE CHANGING. SO THOSER TOX COEPIGENOMIC CHANGES. ANDED THIS SLIDE I PUT THAT -- ABNORMAL THINGS HAPPEN, THEN FIRST THING EFFECTED WILL BE TRANSCRIPTION FACTORS OR CELL CYCLE REGULATORS N MINUTES TO HOURS THAT CAN HELP. IF THOSE EXPOSURES HAVE LONGER LIKE 8 HOURS OR OVERNIGHT, THEN METHYLATION CHANGES AND EPIGENETIC CHANGES YOU CAN SEE. HERE I HAVE NOT SHOWN BUT IN 24 HOURS OR TWO DAYS, YOU WILL SEE MOT BOLLIC CHANGES. THEN ONLY GENETIC CHANGES COME. THAT EMPHASIZES THAT IF WE CAN DETECT THOSE CHANGES EARLY, THEN WE CAN DO SOMETHING ABOUT THE DISEASE. AND HERE WE HAVE SHOWN LIKE IN DIFFERENT CANCERS THE WAY ABOUT GENETIC INFORMATION WE KNOW SIMILARLY NOW ABOUT EPIGENETICS THAT INFORMATION IS COMING. AND IN FACT, CERTAIN GENES HAVE BEEN IDENTIFIED WHICH REGULATE METHYLATION BUT THESE MUTATIONS HAVE BEEN DEPORTED. SO THEY ARE GOING IN SOME CASES BOTH WAYS. PETER JONES AND ANDREW FEINBERG, PETER JONES AT MICHIGAN AND ANDREW FEINBERG IN JOHNS HOPKINS, THEY WERE THE PIONEERS WHO STARTED THINKING ABOUT EPIGENETIC REGULATION. THEY SAW THAT WHEN ACTIVE TRANSCRIPTION IS THERE, THEN HISTONE IS ACETYLATED. INACTIVATION IT STARTS GETTING DEACETYLATION AND AT COMPLETE SILENCING IT GETS METHYLATED BY DNA METHYLATION TRANSFERASE. IF YOU SEE CHROMATIN, THEN CHROMATIN IS YELLOW COLOR SHOWS ACETYLATION BUT GRADUALLY THIS RED COLOR METHYLATION STARTS AND MANY OTHER TRANSCRIPTION FACT EXPOSE GENE REGULATORY FACTORS COME AND THESE CHROMATIN GET SO COMPACTED THAT TRANSCRIPTION STOPS AND THAT IS HOW EPIGENETIC REGULATION WORKS. AND WHEN METHYLATION IS ALSO DONE, THEN ONE IS MENTAL HEALTH LATED AT ONE TIME AND ANOTHER AT ANOTHER TIME -- METHYLATED -- SO WHENEVER YOU DO SUCH KIND OF EXPERIMENTS OF BOTH STRANDS SHOULD BE SEQUENCED. AT DIFFERENT STAGES OF CANCER DEVELOPMENT, THESE ARE THE MUTATIONS BUT IN EPIGENETIC CHANGES, OVERALL INITIALLY BECAUSE OF LINE AND SIGN SEQUENCE WHICH IS COVER ABOUT 90% OF THE GENOME, THEY ARE ALREADY METHYLATED. SO GRADUALLY WITH DISEASE DEVELOPMENT OR LIFELONG, GLOBAL HYPOMETHYLATION YOU WILL SEE BUT FOR SPECIFIC GENE, CHROMATIN GETS HYPOMETHYLATED AND HIS STONE MODIFICATION INCREASE IN CANCER. SO THIS IS ONE PAPER WHERE THEY HAVE MEASURED THAT LINE ONE METHYLATION STATUS IN PROSTATE CANCER, HEART INCREASES. SO VERY SYSTEMATICALLY IT WAS DONE TO SHOW LINE 1. THESE ARE ALSO CALLED JUMPING GENES. SO INITIALLY THEY JUST KNEW THAT THEY WILL GO SOMEWHERE BUT BECAUSE OF EPIGENETIC REGULATION, THIS HAPPENS. METHYLATION ALSO ACCIDENT HAPPEN IN THREE WAYS EITHER ABNORMAL INCREASE OR DECREASE OR NO CHANGE. IN INCREASE UNIQUE TUMOR SUPPRESSOR GENES, EITHER METHYLATION OF BOTH ALLELES OR ONE ALLELE AND DNA IMPRINTING AND ANOTHER IS METHYLATED N ABNORMAL DECREASE IT HAPPENS IN ONCOGENES. OR LATENT VIRAL ACTIVATION. IF YOU REMEMBER IN EARLY 90s, WHEN GENE THERAPY JUST CAME, THEN RETROVIRAL VECTORS WERE USED TO INTRODUCE HEALTHY GENE INTO THE OTHER RECOMBINANT TECHNOLOGY. SINCE RETROVIRUSES WERE USED SO MANY TIMES, CHROMATIN, LTR. SO THOSE GOT HYPERMETHYLATED AND INACTIVATED THAT'S WHY THE VECTOR DID NOT WORK AND RECOMBINANT DNA ALSO DID NOT WORK. BUT AT THE TIME, METHYLATION AND OTHER THINGS WERE NOT VERY WELL CHARACTERIZED. NOW WE KNOW THAT. NOW SUCH VECTORS ARE CREATED WHERE THAT PROBLEM DOES NOT COME. WHERE THERE ARE NO CHANGES, THEN CHEMICAL INDUCED MUTATIONS OR POOR REFAIR SO THESE ARE DIFFERENT COMBINATIONS OF POSSIBILITIES WHICH CAN ARISE DUE TO DNA METHYLATION. HERE AFTER MORE RESEARCH DIFFERENT GENES HAVE BEEN IDENTIFIED WHICH ARE ENROLLED IN EPIGENETIC REGULATION BUT SOME GENETIC CHANGES HAVE ALSO BEEN DEPORTED. ALTHOUGH THIS QUESTION COMES FROM WHETHER GENETICS CAME FIRST OR EPIGENETICS CAME FIRST, BUT WHEN WHOLE EPIGENOME ROADMAP INITIATIVE WAS STARTED AND IN NORMAL CELLS EPIGENETIC PROFILING WAS DONE, THEN IT WAS FOUND THAT EPIGENETIC CHANGES CAME FIRST. BUT NOW WE WANT TO KNOW HOW THEY ARE CORRELATED. EVEN IN DIFFERENT NETWORK OR PATHWAY DIFFERENT GENES OR PATHWAY HAVE BEEN CHARACTERIZED IN TERMS OF WHAT KIND OF EPIGENETIC CHANGES ARE THERE. HERE I HAVE SHOWN INTEGRIN SIGNALING. NOW 10 YEARS AGO WE DID NOT KNOW ABOUT microRNA MUCH. THEY WERE JUST REPORTED IN ANIMALS AND HUMAN AND NOW WE KNOW THAT EVEN CANCER SPECIFIC microRNAs ARE THERE. THESE ARE 25 NUCLEOTIDE SMALL RNA MOLECULES WHICH WERE VERY STABLE AND BECAUSE OF THEIR SECONDARY STRUCTURE, THEY CAN BE USED IN EPIDEMIOLOGY OR EPIGENETICS BY TWO WAYS, EITHER YOU DO microRNA PROFILING AND YOU KNOW WHICH GROUP OF MICRORNA ARE INCREASING OR DECREASING. BESIDES THAT YOU CAN TELL WHETHER SOME DISEASES OR CANCER IS DEVELOPING OR NOT OR RESPONSE TO THERAPY. OR, THOSE GENES WHICH ARE CODING FOR microRNA F THERE IS ALSO ANY POLYMORPHISM, THAT ALSO YOU CAN FOLLOW. microRNA, THEY EITHER INCREASE OR DECREASE SO FOR IN DIFFERENT DISEASES, THAT PEOPLE HAVE FOLLOWED, SO FOR LUNG CANCER microRNAs WILL BE DIFFERENT THAN LIVER CANCER AND ANOTHER CONCEPT IS ALSO COMING ABOUT EXOSOMES. SO SOMEHOW AMONG ALL RNA, microRNA GETS CONCENTRATED IN EXOSOMES. SO FROM THAT WE COLLECT FIRST OF ALL NON-INVASIVELY AND THEN microRNA CAN BE CHARACTERIZED AND CAN BE USED FOR CLINICAL PURPOSES. SO THIS IS THE ONE WE KNOW BEFORE SOMETIME, EXTRACELLULAR EXOSOME AND HOW WE CAN UTILIZE THAT. SO A LOT OF RESEARCH IS GOING ON. AND THOSE EXOSOMES CONTAIN NOT ONLY microRNA, SOMETIME DNA ALSO THERE OR PROTEIN OR METABOLITES. SO HOW THEY CAN BE UTILIZED. HISTONE AS I MENTIONED FOUR KINDS OF TARGETS ARE THERE AND THESE ARE THE TAILS OF THESE HISTONES WHICH ARE MODIFIED WHETHER AT LYSINE OR OTHER POSITION AND THESE MODIFICATIONS ARE SHOWN WHICH IN DIFFERENT CANCERS THOSE HAVE BEEN DEPORTED. WHEN WE INITIATED ROADMAP EPIGENOMIC PROGRAM AT NIH, THEN WHAT WE DID, WE GAVE CONTRACT TO COMPANIES TO RAISE MONOCLONAL ANTIBODIES AGAINST THESE MODIFIED EVIDENT MIGHTIES SO THEY CAN BE USED FOR SCREENING PURPOSES. AND THAT WAS DISTRIBUTED TO DIFFERENT INVESTIGATORS. AND IN THOSE HIS STONE MODIFICATIONS, SOME WILL BE FOR RIGHTING INSTRUCTIONS AND SOME WILL BE FOR REMOVING SO ALL HAVE BEEN CHARACTERIZED AND ALONG WITH HIS STONE, OTHER PROTEINS ARE ALSO BEING CHARACTERIZED AND NOW TECHNOLOGY EXISTS LIKE IT IS COURTSHIP. SO BY IMMUNOTRANSPORTATION AND OTHER TECHNIQUES, YOU CAN IDENTIFY FIRST BY BREAKING CHROMATIN AND THEN TRANSPORTATION THAT WHICH CHROMATIN OR MODIFICATIONS ARE THERE AND AT DIFFERENT TIMES YOU CAN IDENTIFY AND SEQUENCE IN WHICH SEQUENCE WHICH HIS STONE MODIFICATIONS ARE IMPORTANT. AND CANCER RELATED HIS STONE MODIFICATIONS MOST OF THEM ARE ONLY 9-11. SO IF ANYBODY STARTS ANY PROJECT FOR SCREENING PURPOSES OR OTHER PURPOSES, THEN WE DEMAND THAT THOSE SHOULD BE USED. AND HERE THEY ARE SHOWN LIKE AT LYSINE 4 OR LYSINE 9 OR 27. WHERE THIS IS THERE AND WHERE THEY ARE ACTING HOW THEY ARE MODIFIED. SO ALL OF THOSE OF COURSE CHARACTERIZED. AND THESE ARE USED FOR DIAGNOSTIC PURPOSES ALSO. HIS STONE MODIFICATIONS AND TO COMBINE AND PROMOTE THE FIELD TIME TO TIME I HAVE EDILATEED DIFFERENT BOOKS EITHER ON CANCER EPIGENETICS OR CANCER EPIDEMIOLOGY FOR HOST SUSCEPTIBILITY FACTORS OR THIS YEAR WAS ON PROGRESSES AND CHALLENGES IN PRECISION MEDICINE. EVERY INDIVIDUAL IS DIFFERENT SO HOW WE CAN UTILIZE THIS INFORMATION IF A DOCTOR FOLLOWS A PATIENT AND TAKES SAMPLES AGAIN AND AGAIN. I WAS INTERVIEWED ONE TIME BY NATURE TO KNOW WHY EPIGENETICS IS IMPORTANT COMPARED TO GENETICS. SO THEN I EMPHASIZED THAT IF YOU HAVE MUTATION CHANGE NEGLIGENCE GENE, YOU CAN NOT GO BACK. JUST YOU CAN USE THAT TO TELL WHAT DISEASE WILL DEVELOP AND WHAT CAN HAPPEN. BUT THESE EPIGENETIC CHANGES, METHYLATION AND HIS STONE, YOU CAN REVERSE. SO EPIGENETICS HAS SLIGHT EDGE OVER GENETICS. AND THEN NEXT YEAR AGAIN I WAS INTERVIEWED BY THE SAME JOURNAL THEN. BY THAT TIME, CERTAIN DRUGS WERE INTRODUCED OR IDENTIFIED WHETHER THEY WERE DIMETHYLATING OR HISTONE MODIFIED. THEY CAN DO HISTONE MODIFICATIONS. SO THOSE WERE ALSO IDENTIFIED AND DIFFERENT PHARMACEUTICAL COMPANIES THEY STARTED WORKING ON THOSE DRUGS. WE CALL THOSE EPIGENETIC INTEGRATES. IN METHYLATION PROJECTS, DIFFERENT KINDS YOU HAVE TO KEEP IN MIND AS DIFFERENT KIND OFFED CONTROL TO REDUCE FALSE NEGATIVE OR FALSE-POSITIVE. LIKE FERTILE METHYLATION CONTENT OR AT A SPECIFIC STAGE OR PATTERN OR PROFILE OF METHYLATION OF EITHER SPECIFIC GENES OR A NUMBER OF GENES. OR PATTERN IN WHOLE EPIGENOME. BUT IF ALL THESE CONTROLS ARE PROPERLY MAINTAINED, THEN METHYLATION PROFILING WILL BE VERY ACCURATE. OFFED STEVE WHO IS IN JOHNS HOPKINS, WORKS ON CLINICAL EPIGENOMICS OR TRANSLATIONAL EPIGENOMICS MODEL AND THEY CHARACTERIZED MORE NON HISTONE AS DIFFERENT TRANSCRIPTION FACTORS AND OTHERS IN HIS STONE. THEIR SEQUENCE WHEN THEY COMBINE AND WHEN THEY ARE RELEASED AND THEY DO THAT KIND OF WORK IN H3 HISTONE K27 TRIMETHYLATED. AND THEN THE GENE WILL BE INVOLVED IN DIFFERENTIATION. OR IF NEXT TERMINIS IN THIS CASE S3K9 METHYLATION, THEN CHANGE WILL BE PERMANENT. SO THESE KINDS OF BASIC RESEARCH IS ALSO GOING ON. NOW DIFFERENT STAGES OF DEVELOPMENT OF CANCER LIKE PROGRESSION, EARLY DETECTION, THEN DIAGNOSIS OR THERAPEUTIC TIME, IN THESE STAGES, DIFFERENT EXFOLIATE CELLS COME. SO IF THESE SAMPLES ARE COLLECTED, THEN MANY MARKERS CAN BE CHARACTERIZED FROM THAT. FOR DIFFERENT TYPES OF CANCERS AFTER DOING INVESTIGATORS DONE IN DIFFERENT SET OF INSTITUTES, GROUP OF GENES HAVE BEEN IDENTIFIED WHICH IN THESE CANCERS WILL BE HYPERMETHYLATED. SIMILARLY, OTHER KINDS OF PROTEINS ARE THERE IN WHICH METHYLATION CHANGES OR OTHER CHANGES ARE THERE. THOSE ALSO HAVE BEEN CHARACTERIZED VERY WELL. AGAINST THOSE PROTEINS OR METHYLATION CHANGES IN DIFFERENT DRUGS ARE BEING DEVELOPED, THESE ARE THE ONES FOR METHYLATION CHANGES IN DIFFERENT TRIALS OR HISTONE CHANGES. SOME OF THE PROMISING RESULTS ARE ALSO COMING. ALTHOUGH SOMETIMES SOME ADVERSE REACTION LIKE DEHYDRATION, DIARRHEA, NAUSEA, VOMITING, THOSE YOU SEE. BUT STILL AGAINST HISTONE ACETEL TRANSFERATION, AGAINST THAT, THESE ARE THOSE DRUGS WHICH ARE IN PIPELINE WHETHER IT IS JOHNSON & JOHNSON OR SMITHKLINE OR ASTRAZENECA, ALL HAVE PROGRAMS AGAINST THESE EPIGENETIC DRUGS. IF YOU GET A CHANCE TO GO TO AMERICAN SOCIETY OF CLINICAL ONCOLOGY, THE RESULTS ARE PRESENTED THERE. AND THESE INHIBITORS BELONG TO DIFFERENT CLASSES, SHORT GENE FATTY ACIDS OR CYCLIC PEPTIDES OR BEN ZA MIDES. SAME WITH HISTONE, DEACETYLASES ARE BING CHARACTERIZED AGAINST DIFFERENT FORMS ALSO. THEY ARE BEING DEVELOPED. SO THESE INHIBITORS PROVIDE A NOVEL CLASS OF ANTI-CANCER DRUGS AND SOMETIMES THEY WORK AS RADIO SENSITIZERS LIKES REGULAR TREATMENT, TREATING IF YOU PUT IN MANY PATIENTS WILL NOT RESPOND BUT IF YOU KEEP EPIGENETIC PROGENITOR FIRST THEN THE DRUG THEN IT STARTS WORKING. AN EXAMPLE, ONE OF THIS IS THERE WE HAD METHYLATION DRUG AND HIS STONE DRUG THAT WAS USED. IN THOSE PATIENTS MORE THAN 50 WHERE NO OTHER DRUG WAS WORKING. SO THIS COMBINATION WAS GIVEN AND BY SEQUENCING, THIS METHYLATION WAS DONE AND CHIP ON CHIP ANALYSIS WAS DONE ON DAY ONE, 10 AND 28 AND THEY STARTED RESPONDING. SIMILARLY, IN IN A ANOTHER EXAMPLE, COMBINATION OF 5 ASA SIGHTA DEAN, VALPROIC ACID&FOR MYELOID LEUKEMIA AND MYELOID DISPLASTIC SYNDROME WAS USED. THEN THEY OBSERVED THAT THESE DRUGS CAN IMPROVE THE CANCER DEVELOPMENT. AND AT NCI, WE HAVE SEVERAL CLINICAL TRIALS ARE GOING ON. HERE I HAVE SHOWN FOR HISTONE INHIBITORS. WHETHER THESE ARE SOLID TUMORS OR LEUKEMIA OR LYMPHOMA, BREAST CANCER, OR GLIOBLASTOMA, THESE ARE DIFFERENT TRIALS IN WHICH THESE EPIGENETIC INHIBITORS ARE BEING TRIED. SIMILARLY FOR METHYLATION INHIBITORS ALSO ON SOLID TUMORS OR LEUKEMIA OR MYELOID LEUKEMIA OR PROSTATE CANCER THESE ARE BEING TRIED. AND THAT I ALREADY MENTIONED SHEDDING ALL THESE COMPANIES HAVE MANY INHIBITORS IN THEIR PIPELINE AND THE IDEA IS THE SAME LIKE THIS INHIBITOR SHOULD BE TRIED EITHER ALONE OR IN COMBINATION. ONLY EPIGENETIC INHIBITORS OR OTHERS. AND SEVERAL STUDIES SHOW THOSE PROMISING RESULTS. GRADUALLY, FDA ALSO FOUND THOSE STUDIES USE ENVELOPE FOUR EPIGENETIC INHIBITORS, TWO FOR METHYLATION, TWO FOR HISTONES. THOSE ARE APPROVED BY FDA. LATER ON, NOW WE INDIVIDUAL ALL TOGETHER SIX INHIBITORS THERE WHICH ARE FDA APPROVED. SO IT IS NOT JUST LIKEY EPIGENETICS WE ARE UNDERSTANDING, BUT THAT IS IN CLINIC ALSO. AND NATURE REVIEW PUT SOMETHING ABOUT CLINICAL TRIALS WHERE EPIGENETICS THERAPY IS GOING ON. SO THAT YOU CAN SEARCH ON YOUR OWN IF YOU ARE INTERESTED. AND THERE YOU FIND THEN INFORMATION WHAT WAS THE COMBINATION WHICH WAS GIVEN FIRST, HOW MUCH WAS THE DOSE, WHAT KIND OF BACKGROUND OF PATIENT WAS THERE? ALL OF THOSE KINDS OF INFORMATION IS THERE. AND TIME TO TIME, WE ALSO WRITE ABOUT HOW THEY ARE DOING IN DIFFERENT KIND OF CANCER. IN THOSE STUDIES WHICH WE SUPPORT FROM OUR PROGRAM. LIKE THIS IS COMBINATION THERAPY OF EPIGENETICS FOR LUNG CANCER. THIS WAS FOR HEME LOGICAL EPITHELIAL TUMOR CELLS. SO NOW I WILL TELL DIFFERENT KIND OF CANCERS SO EPIGENETICS HAS BEEN STUDIED MORE. THIS IS FOR COLORECTAL CANCER IN WHICH METHYLATION CHANGES IN WHARF GENES ARE THERE THEY ARE SHOWN. SOME ARE AT VERY EARLY STAGES AND SOME ARE AT LATER STAGES BUT ALONG WITH GENETIC CHANGES AND EPIGENETIC CHANGES, WE FOLLOW MICROSTABILITY ALSO AND IN FACT N COLON CANCER, CPG ISLAND, METHYLATED PHENOTYPE OR SOMETIMES PEOPLE CALL IT SIMPLE PHENOTYPE. THAT WAS OBSERVED. WHAT HAPPENS THAT LEFT SIDE OF COLON BACHES DIFFERENT THAN RIDE SIDE OF -- THAN RIGHT SIDE OF COLON. TO THE eGFR RECEPTOR OR BFRAF MUTATION OR THIS MICROSTABILITY HIGH OR LOW BUT METHYLATION PATTERN, THESE SITES ARE DIFFERENT AND THEY RESPOND ALSO DIFFERENTLY TO DIFFERENT INHIBITORS. SO IN THAT ONLY BY EPIGENETIC CHARACTERIZATION WAS FOUND THAT COLON CANCER SHOULD BE TREATED DIFFERENTLY. NOW ANOTHER IS ALSO COMING OFF MICROBIOME. WE ARE MICROBES MAKE THEIR COLONIES IN COLON AND MAKE BIOFILM. SO WE WANT TO INTEGRATE THAT DATA WITH THIS AND SEE WHETHER THAT CAN IMPROVE OUR TREATMENT OR NOT. BUT JUST BY METHYLATION PROFILING, WHEN THAT WAS DONE, THEN KRAS MUTATION OR B-RAF MUTATION OR METHYLATION, THEY CAME IN A GROUP. AND WE COULD IDENTIFY A GROUP OF GENES WHICH THEY ARE USED ALONG WITH MSI, THEY CAN TELL WHO IS AT HIGH RISK OF DEVELOPING COLORECTAL CANCER. SO IT IS NOT LIKE SCREENING ONLY I YOU HAVE TO DO BUT OTHER NON-INVASIVE TECHNOLOGY ALSO YOU CAN DO FOR DETECT COLORECTAL CANCER. IN EML AND ALL, BASED ON METHYLATION PATTERNS PEOPLE CAN BE DISTINGUISHED BETWEEN ALL OR AMLN CASE OF LUNG CANCER, ALONG WITH PROTEOMICS MARKER, THESE EPIGENETIC MARKERS WERE USED AND EVEN IN SPIT UM YOU CAN DO THE TEST AND STEVE HAS DONE THIS KIND OF WORK. ASBESTOS AND MESOTHELIOMA. THOSE TWO GROUPS CAN BE IDENTIFIED AND THEY HAVE BEEN DONE IN LARGE NUMBER OF PEOPLE. IN ESOPHAGEAL CANCER, BETTER IS EARLY STAGE. SO METHYLATION PATTERN IN 20 GENES OR SO IF YOU FOLLOW, THAT SOME GENES ARE METHYLATED AT EARLY STAGES AND SOME ARE LATER STAGES, SO LONG YOU FOLLOW THE SAME PATIENT YOU CAN TELL THAT PERSON IS AT HIGH RISK OF DEVELOPING THIS CANCER. AND THAT METHYLATION PROFILING CAN BE CORRELATED TO SURVIVAL ALSO. AFTER TREATMENT WHETHER PATIENT IS SURVIVING OR NOT. MANY TIMES PEOPLE ASK THAT FOR COHORT OF CLINICAL TRIALS WHY WE COLLECT INFORMATION REGARDING PATIENT HISTORY OR EXPOSURE HISTORY OR OTHERS. BUT IT IS VERY IMPORTANT. BECAUSE IF SOMEBODY IS ALCOHOLIC, THEY HAVE KRAS MUTATION LONGSTANDING DIABETES, AND FOR PANCREATIC CANCER, CURRENTLY WE DON'T HAVE EARLY DETECTION MARKERS BUT ALONG WITH THOSE FEATURES, THEY GET HYPERMETHYLATED THEN IT MEANS THOSE PEOPLE ARE AT HIGH RISK OF DEVELOPING PANCREATIC CANCER. OTHERWISE PANCREATIC CANCER ARE SUCH THAT IN ONE OR TWO YEARS BY THE TIME IT IS DETECTED, IT IS TOO LATE. FOR BREAST CANCER, LUNG CANCER, COLON CANCER, AND SOME OTHER CANCERS, IT TAKES 15-20 YEARS BUT THESE ARE SUCH VERY FERTILE CANCERS. IN BREAST CANCER, TREATMENT CAN BE FOLLOWED BY BASED ON METHYLATION PROFILING. NOW COMES THOSE INFECTIOUS AGENTS MANY INFECTIOUS AGENTS LIKE HPV, SB40, H. PYLORI, HAVE BEEN ASSOCIATED WITH MANY OTHER CANCERS. IN FACT, IF YOU SEE ALL CANCERS THEN IN 15% OF TOTAL CANCERS, INFECTIOUS AGENTS ARE INVOLVED. AND IN THAT LATENCY ASSOCIATED NUCLEAR ANTIGEN OR EPSTEIN-BARR VIRUS, THEY ARE THE MAIN GENES WHICH ARE INVOLVED. SADLY FOR PAPILLOMA VIRUS, EBV OR LIVER CANCER, WHOLE METHYLATION PROFILING HAS BEEN DONE. WHY WE ARE INTERESTED IN THESE KINDS OF RESEARCH? JUST BY PATHOLOGICAL EXAMINATION OR HISTOLOGY YOU CAN NOT TELL A PERSON WILL DEVELOP THOSE CANCERS OR NOT. BUT IF WE KNOW THIS PROFILING THEN, WE KNOW THAT THE PERSON IS AT HIGH RISK. SO HERE LIKE IN HPV, EARLY GENES OR LATE GENES ARE THERE. WHATEVER GENES WHEN IT IS METHYLATED AND WHAT THE THE EXTENT OF METHYLATION AT DIFFERENT STAGES. THOSE HAVE BEEN CHARACTERIZED COMPLETELY. AND TO PROMOTE THIS AREA, WE HAVE PUT ON HIV/AIDS OR OTHER WIDE METHYLATION ALSO, THAT AREA WE ARE PROMOTING, OR FOR LIVER CANCER IN THAT EP TITIS B OR C, THOSE ARE BEING CHARACTERIZED. AND INHIBITORS, MOSTLY IN ASIAN AND JAPANESE POPULATION IS THERE SO ONE GENE WAS OBSERVED WHERE HYPERMETHYLATION WAS OBSERVED ONLY IN JAPANESE POPULATION. SO SOMETIMES SOME CHANGES ARE VERY MUCH POPULATION BASED. SOME ARE VERY COMMON LIKE FORWARD HYPOMETHYLATED CARCINOMA, THIS GENDER OF GENES GETS HYPERMETHYLATED N B-CELL OR D-CELL DURING DEVELOPMENT OR DIFFERENT FUNCTIONS, EPIGENETICS HAS BEEN CHARACTERIZED VERY WELL. AND T-CELL METHYL TRANSFERATION IN CANCER AND OTHER DISEASES, THOSE HAVE ALSO BEEN CHARACTERIZED. NOW IN PROSTATE CANCER, MOSTLY PSAs THE ONE WHICH WAS STILL BEING USED BUT WHEN LEVEL IS LESS THAN 4 NANOGRAM PER ML, THEN DOESN'T KNOW WHETHER THEY SHOULD WAIT OR THEY SHOULD TREAT BECAUSE PROSTATE CANCER IS SUCH IT TAKES LONG TIME SO WHETHER GO FOR SURGERY OR CHEMO OR RADIATION. THEN GS26789P1 METHYLATION CAME THAT IN MOST OF THE CASES THOSE HYPERMETHYLATED GROUPS, THEY INDICATE BETTER RESULTS AND THEN COMPARED WITH PROSTATE CANCER WAS ALSO DONE. THEN EPIGENOMICS, ONE COMPANY WAS THERE WHICH DEVELOPED THIS TEST AND THEY HAD WORKED WITH QUEST DIAGNOSTICS, NOW THEY TO FOR PROSTATE CANCER THAT TEST US AND THEY HAVE DIFFERENT PRICES. IN PLAIDER CANCER, ACTUALLY EXFOLATED CELLS WHICH COME IN URINE, IF YOU COLLECT THAT DOSE HAVE SUFFICIENT AMOUNT OF DNA, WHICH YOU CAN USE FOR METHYLATION PROFILING. SO BLADDER CANCER LIKE LUNG CANCER WITH SMALL ARE AFFECTED SO THAT YOU CAN USE. NOW THAT ALSO HAPPENS TO METHYLATION PROFILEING LIKE UNIVERSITY OF SOUTHERN CALIFORNIA. WITH THAT, MANY TIMES WHAT HAPPENS IS CANCER ONE STAGE IN ONE ORGAN SITE AND ANOTHER STAGE IT IS ON OTHER SITE. OR SOMETIMES SECONDARY CANCER ALSO COMES. SO HE USES AND CAN IDENTIFY WHICH OTHER CANCERS A PERSON IS LIKELY TO DEVELOP OR PREDICTION MODELS TO DEVELOP BASED ON THAT. NOW COMES A LITTLE BIT ABOUT PREVENTION. AS I MENTIONED, EPIGENETIC CHANGES, THOSE YOU CAN REVERSE. SO IN THAT IT IS OUR UNDERSTANDING THAT CANCER SINCE MOST OF THE TIME ENVIRONMENT LIFESTYLE AND DIET AND EXPOSURE, THEY PLAY MAJOR ROLE. SO IF YOU CHANGE THAT, THEN YOU CAN PREVENT CANCER IN 30-40% CANCER CELLS ARE PREVENTIBLE. SO THAT KIND OF RESEARCH WAS DONE AND IN LIVER CANCER, ONE MODEL WAS DEVELOPED. NO CARCINOGEN WAS THERE JUST METHYL DEFICINT MODEL WAS SUPPLIED AND IT WAS VERY SIMILAR TO LIVER CANCER AND THEN IN DIFFERENT FOOD. AND BIOLOGICAL COMPONENTS, THOSE WERE CHARACTERIZED. FOR EXAMPLE IN CINNAMON OR APPLE OR CITRUS OR COFFEE, BROCCOLI, GARLIC, ET CETERA. SO SOME FOOD HAVE DIMETHYLATING PROPERTIES. SOME HAVE HISTONE MODIFICATION PROPERTIES SOME HAVE BOTH. SO WE HAVE INSTITUTE OF ALTERNATIVE MEDICINE WHERE THEY ARE TRYING TO UTILIZE NATURAL FOOD HOW THEY CAN DO IT AND HOW MUCH EPIGENETIC MECHANISM IS GOING ON. I ALSO WROTE ONE ARTICLE ON NUTRITION AND EPIGENETICS TO COVER THAT AREA. NOW COMES WHAT NIH HAS DONE TO PROMOTE THIS AREA. WHEN DR. ZERHOUNI WAS DIRECTOR OF NIH, HE INITIATED A PROGRAM THAT 1.5% OF BUDGET IF ALL INSTITUTE CONTRIBUTE, THEN THAT CAN BE UTILIZED TO UNDERSTAND SUCH BIOLOGY WHICH INSTITUTES CANNOT SUPPORT BUT IT WILL BE VERY HELPFUL. SO IN FIRST ALLOWING MICRO-ENVIRONMENT EPIGENETICS, THESE TWO PROGRAMS WAS PROMOTED BECAUSE EPIGENETICS IN SEVERAL BASE ORDER THAT WAS OBSERVED. BUT IT WAS NOT KNOWN THE WAY WE HAVE IN GENOME FROM HEALTHY PEOPLE ALSO WE HAVE SEQUENCE. IN PROTEOMICS WE HAVE PROTEOMICS PROFILING. BUT FOR METHYLATION PROFILING AND HISTONE AND microRNA AND OTHERS WE DO NOT HAVE. SO THIS EPIGENOMIC ROADMAP PROGRAM WAS INITIATED. AS OF THAT ROADMAP PROGRAM THAT FOR 5-10 MAJOR PROJECTS CAN BE STARTED WHICH ARE OF HIGH RISK, BUT FOR THAT, THEY CAN CONTRIBUTE A LOT IN TRANSLATION OR TRANSFORMATIVE BIOLOGY. SO AFTER THAT, ANOTHER DIRECTORS CAME AND FRANCIS COLLINS CAME AND CHANGED THE NAME TO COMMON FUND. AND AS AN EXAMPLE, YOU CAN SEE THAT IN 2015 AND 16 ALSO ALMOST THE SAME AMOUNT B HALF BILLION DOLLARS SPENT. AND I HAVE BEEN INVOLVED IN THREE MAJOR PROGRAMS FROM THE START. EPIGENOMICS ROADMAP PROGRAM, AND THEN METABOLOMICS AND THEN THIS MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITIES. SO IN THAT WE ARE DOING SUCH RESEARCH WHICH IS FOR HEALTHY PEOPLE, WHAT KIND OF PROFILING IS THERE OR INCREASING THE CAPACITY TO DO THAT KIND OF ANALYSIS, SO THAT IS DONE. AND THESE ARE OTHER PROGRAMS WHICH ARE GOING ON. LIKE SINGLE CELL ANALYSIS IS THERE, GLOBAL HEALTH, SCIENCE AND BEHAVIOR, GENOMIC TUMOR EXPRESSION, ET CETERA.& SO FOR EPIGENOMIC ROADMAP YOU CAN IMAGINE -- AND THESE ARE ALL CONGRESSIONALLY MANDATED PROGRAMS. SO FIRST MONEY WILL GO TO THIS PROGRAM AND THEN IT WILL BE DISTRIBUTED TO OTHERS. SO IN 2008, WE STARTED AND WE DID IT THAT FOR MAPPING OF DIFFERENT SITES FOR EPIGENETICS AND LET ME SHOW YOU THE SLIDE. AND NATURE COVERED TWO YEARS AGO, WHOLE EPIGENOMIC ROADMAP, WHAT KIND OF DATA WE GOT. SO SINCE FOUR DIFFERENT ORGANS DIFFERENT EPIGENOMIC PROFILING, SO ABOUT 112 KINDS OF CELLS WERE CHARACTERIZED FROM BRAIN, BREAST, LIVER, DUE ADENOMA. SO THESE ARE THE SITES FROM WHICH CELLS WERE COLLECTED AND PROTOCOLS WERE DEVELOPED AND THEN EPIGENOMIC DATABASE WAS CREATED AND COMPLETE MEANS LIKE METHYLATION PROFILING, HISTONE PROFILING, MICRORNA AND DNA MAPPING. SO THESE ARE THE TYPES OF CELLS SHOWN HERE WHICH WERE TAKEN AND SOME FROM STEM CELLS ALSO. SO NOW WE HAVE SOME REFERENCE POINT SO THAT WE CAN USE THAT IF SOMEONE DEVELOPS A DISEASE THAT WHAT KIND OF CHANGES ARE IN HEALTHY PEOPLE, WHAT KIND ARE IN DISEASE PERSON. AND THROUGH THAT SEVERAL HIGH-QUALITY PAPERS WERE ALSO PUBLISHED DURING THAT TIME. ON PARALLEL INTERNATIONALLY ALSO CELLULAR FIRST CONDUCTED AND ONE OF THE EXAMPLES IS INTERNATIONAL HUMAN EPIGENOME CONSORTIUM OR IHECN EUROPE IT WAS DEVELOPED AND WE PARTICIPATE IN THAT SO THERE IS NO WORK LEFT. THEY WANT TO DO A MODEL ORGANISM US AND OTHER DISEASE THEY WANT TO DEVELOP THEIR IDEA WAS THAT ABOUT 1000 EPIGENOME THEY WILL BE DOING. SO WHEN WE HAD OUR FIRST MEETING, THESE ARE THE COUNTRIES WHO PARTICIPATED IN THAT. AND THEN FUNDING AGENCIES WERE ALSO DIFFERENT LIKE WE ARE FUNDING EPIGENOME ROADMAP WHILE OTHER PEOPLE CAN AND INDUSTRY SUPPLIED MOSTLY EQUIPMENT AND OTHER SOURCES AND NATURE AND SCIENCE COVERED THAT. AND EVERY YEAR IHECK HAS ANNUAL MEETING WHERE WE UPDATE EACH OTHER AND AMERICAN ASSOCIATION OF CANCER RESEARCH, THEY ALSO COVER THAT. THIS IS THEIR WEBSITE SO THEY KEEP TRACK OF WHATEVER IS HAPPENING IN EUROPE, ASIA AND OTHER PLACES. WE KEEP TRACK OF U.S. BUT WE EXCHANGE VIEWS AND GOALS AT LEAST NICE A YEAR. NOW OTHER CHALLENGES WHICH ARE COMING TO BRING TO CLINIC, HOW NIH AND NCI WE ARE DOING. SO WE USUALLY WRITE ARTICLES IN WHICH WE WRITE THE FUTURE RESEARCH PROGRAMS WHERE PEOPLE SHOULD DO RESEARCH. SO THIS WE DID ON EPIDEMIOLOGICAL TRENDS AND CHALLENGES OR MOLECULAR PROFILING HOW TO USE THAT FOR PERSONALIZED MEDICINE OR PRECISION MEDICINE. AND THEN INITIATING THIS PROGRAM, THIS WAS CALLED PRECISION MEDICINE INITIATIVE. SO IN THAT IDEA WAS THAT ONE MILLION PEOPLE WILL BE ENROLLED AND THERE ELECTRONIC RECORDS WILL BE MAINTAINED FOR THEM FROM THE START AND WHEN OUR TREATMENT IS THERE AND WHEN THEY ARE UNDERGOING SOME KIND OF ANALYSIS, AND THEIR DATA WILL BE AVAILABLE TO ALL. SO THIS WAS INITIATED AND THEN RECENTLY THE NAME WAS CHANGED JUST ALL OF US, THE PROGRAM IS THE SAME BUT THIS IS ALSO DONE BY CONGRESSIONALLY MANDATED PROGRAM. SINCE THOSE KINDS OF INFORMATION ARE COMING LIKE ONE DRUG OR ONE NOT WORK FOR ALL AND MORE AND MORE AND MORE WHENEVER YOU GO TO A DOCTOR, THEY RECORD ELECTRONICALLY YOUR INFORMATION AND WHATEVER IS NOT RECORDED, THAT ALSO WE ASK THEM TO PUT THAT FOR FUTURE SO IN THESE, WILL BE VERY USEFUL IN FUTURE. OTHERWISE AS IT HAPPENS HERE ALSO WE HAVE BIO INFORMATICS CHALLENGES AND RECRUITMENT AND OTHER AND WE THINK WE ARE IN RIGHT DIRECTION. THEN CAME 21ST CENTURY CURE ACT IN WHICH MOONSHOT PROGRAM CAME FROM NCI AND NHGRI, GENOME RESEARCH INSTITUTE ALSO, PARTICIPATED IN THIS PROGRAM. THESE TWO INSTITUTES WERE GIVEN ADDITIONAL MONEY, ABOUT 350 MILLION DOLLARS AND THIS IS ALSO FOR MANY YEARS. HERE IDEA WAS WHATEVER RESEARCH IS GOING ON IN TRANSLATIONAL EPIGENETICS OR OTHER KIND OF PROGRAMS, THEN HOW THEY CAN MAKE THE SPEED FASTER. HOW YOU CAN BRING THAT QUICKER TO THE CLINIC. SO THAT HAS BEEN GOING ON. NOW WE HAVE RETAINED THOSE PROGRAMS WHICH ARE CALLED FUNDING OPPORTUNITIES ANNOUNCEMENT OR RFAs AND THEN PEOPLE ARE GOING TO SUBMIT THEIR PROJECTS AND BY MAYBE NEXT YEAR, WE ARE GOING TO FUND THIS PROGRAM. AND TO PROMOTE THAT PERSONALIZED MEDICINE, OTHER ARTICLES WE WRITE ALSO OR IN CANCER EPIDEMIOLOGY. THIS IS THE WAY TO IDENTIFY DIFFERENT KINDS OF RISK FACTORS OR CAUSATIVE AGENTS. WE PROMOTE THAT EPIDEMIOLOGY A LOT BY WHITING THESE KINDS OF ARTICLES OR STEM CELLS HOW TO UTILIZE THAT. SO WHAT ARE THE CURRENT RESEARCH OPPORTUNITIES AND CHALLENGES BASED ON WHAT I GAVE YOU BACKGROUND? WHETHER THESE EPIGENETIC MARKERS OR THESE PROFILING, THEY CAN HELP US IN IDENTIFYING NEW RISK FACTORS OR ESTIMATE WHAT FACTORS WE HAVE. THOSE ARE GOOD FOR DIFFERENT RISK AND ETHNIC GROUPS. THEN WHEN CASE CONTROL STUDIES OR COHORT STUDIES OR WHICH STUDY DESIGN WE SHOULD FOLLOW TO DO THAT KIND OF RESEARCH. HOW MUCH CORRELATION IS THERE IN GENETICS AND EPIGENETICS AND WHETHER RACIAL OR ETHNIC SPECIFIC microRNA OR NON CODING RNA WE CAN IDENTIFY. OR HOW WE CAN USE THESE KINDS OF INFORMATION FOR DIFFERENT SUBCATEGORIES OR SUBTYPING OF CANCERS. AS YOU KNOW IN BREAST CANCER, 11 KINDS OF CELLS ARE IN BREAST CANCER. SO THAT SUBTYPING MANY TIMES FOR THOSE PATHOLOGISTS WHO ARE TRAINED EARLIER, IT IS VERY DIFFICULT FOR THEM DISTINGUISH. AND IN RESPONSE TO TREATMENT DIFFERENTLY BUT MY MOLECULAR CHARACTERIZATION, IT CAN BE DONE. THESE ARE MY COLLABORATORS AND I WANT TO LEAVE WITH THIS CODE THAT OUR GENOME AND WILL SUPERIMPOSED EPIGENETIC CODE. THIS IS A JOURNEY WE'VE EMBARKED ON, ONE THAT IS BEHAVED ROAD BLOCKS, BUT ALSO WITH MANY AMAZING DISCOVER SPEC SUCCESS STORIES, BOTH IN CANCER MEDICINE AND CANCER SCIENCE. WE ARE PRIVILEGED TO BE PART OF THESE AND TO SHARE THEM WITH ALL OF YOU. THANK YOU. [ APPLAUSE ] >> WHAT DO YOU THINK IS THE BEST TARGET, METHYLATION OR HISTONE? >> IN DIFFERENT CANCERS THEY ARE GETTING DIFFERENT RESULTS. SOMETIMES HISTONE AND SOMETIME METHYLATION. BUT BEST RESULTS SO FAR IN CLINICAL TRIALS ARE COMING FROM THOSE WHERE REGULAR AGENTS, THEY ARE NOT THAT MUCH EFFECTIVE BUT IF YOU PRETREAT WITH HISTONE AND THEN AFTER SOMETIME INTRODUCE METHYLATION, THEN THEY GET GOOD RESULTS. SO IT IS A MATTER OF WHICH WE SHOULD START FIRST, WHICH SECOND, AND HOW MUCH DOSE WE SHOULD USE. BUT MANY MORE ARE COMING AND ALSO ESPECIALLY IN HISTONE DEACETYLASE, DIFFERENT FORMS HAVE BEEN IDENTIFIED. SO PHARMACEUTICAL COMPANIES FOR DIFFERENT FORMS, THEY ARE CREATING THOSE INHIBITORS. BUT THEY ARE COMING VERY WELL AND NOW WE HAVE AT LEAST THIS ESTIMATION, THEY ARE BEING USED. AND MAIN THING WITH THE TIME OR WITH AGE, WE COLLECT SO MUCH SOMATIC MUTATIONS AND SNIPPS AND ALL THOSE, SOME COME WITH DISEASE BUT WE CANNOT GO BACK. BUT IF WE CAN IDENTIFY THESE THEN PROBABLY SINCE THEY ARE REVERSING, THEN IT DOES GOOD. BUT IT STILL BEST WAYS THAT PEOPLE CHANGE LIFESTYLE AND THEN USE THOSE NATURAL FOOD AND THEN I THINK YOU CAN PREVENT AND DO THAT. BECAUSE THEY HAVE INHERENT EPIGENETIC INHIBITING PROPERTIES, MANY OF THOSE FOODS. >> SO DO YOU THINK THAT THE EPIGENETIC PHENOMENA IS MORE IMPORTANT IN THE YOUNG RELATIVE TO THE OLD? >> YES. THAT IS VERY WELL. THAT AT LEAST HAS COME OUT IN THEIR STUDIES THAT ONE-HALF YEAR OLD ECHO PROGRAM WAS INITIATED. ENVIRONMENT AND INFLUENCINGS ON HEALTH, CHILD HEALTH OUTCOME. THE REASON -- AND ALSO TO DO THAT THOSE CENTERS WHICH WANT TO DO THAT RESEARCH, THEY SHOULD HAVE ONGOING STUDIES. SO 84 COHORTS WERE IDENTIFIED AND 34 INVESTIGATORS WERE FUNDED. SO THEY ARE DOING THEIR OWN RESEARCH. BUT WE HAVE COME OUT WITH ONE COMMON PROTOCOL AND COMMON COLLECTION OF MATERIAL LIKE MALE HAIR AND PSYCHOSOCIALIST, INCOME, EDUCATION, ALL THAT DATA IS BEING COLLECTED. WHEN THEY GO TO CLINIC AND WHAT EVER BIOSPECIMEN THEY CAN DO, THAT IS BEING DONE. AND THOSE WILL BE FOLLOWED FOR LONG TIME. OTHERWISE IN DISEASE DIAGNOSIS AND PROGNOSIS, WHAT WAS HAPPENING, WHEN YOU ARE VERY SICK THEN DOCTOR SEE YOU AND THEN BASED ON THAT THEY ARE PRESCRIBING. BUT THEY DO NOT KNOW WHEN IT IS TARGETING OR WHETHER WE CAN STOP THAT EARLY. SO ON EARLY EXPOSEAL EMPHASIS IS VERY MUCH. SO WITH NIEHS, NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES, AND WE WORK TOGETHER. AT NIH LEVEL ALSO. >> THANK YOU. >> WE HAVE SOME ANNOUNCEMENTS. OUR LAST CLASS THROUGH THIS YEAR WILL BE NEXT MONDAY, DECEMBER 4. AND WE'LL BE HAVING LECTURES ON PANCREATIC CANCER AND NANOTECHNOLOGY. AND UNFORTUNATELY, I'LL BE OUT OF TOWN THEN, SO DR. ZEA WHO GAVE THE BREAST CANCER LECTURE, SHE WILL BE HERE DISTRIBUTING THE HANDOUT AND INTRODUCING THE SPEAKERS. AND THEN WHEN THE CLASS IS OVER, IT'S POSSIBLE TO GET A CERTIFICATE OF COMPLETION OF THE COURSE AND SO WHAT WE'LL BE DOING IS, BY DECEMBER 11, WE'LL BE POSTING THE FINAL EXAM, AND IT IS A MULTIPLE GUESS EXAM GRADED BY THE COMPUTER. IT HAS ONE QUESTION FROM EACH OF THE LECTURES. IF YOU GET 70% OF THE ANSWERS CORRECT, THEN YOU PASS. AND THE EXAM WILL BE ON LINE FOR ABOUT A MONTH AND THEN HOPEFULLY AT THE END OF JANUARY, WE'LL BE PRINTING THE CERTIFICAT. USUALLY ABOUT 40-50 PEOPLE GET THE COURSE AND GET THE CERTIFICATE. SO IF YOU HAVE ANY QUESTIONS ON THAT, CONTACT ME. AND OUR LAST LECTURE TODAY IS BY DR. OLAKU, OF THE DIVISION OF CANCER TREATMENT AND DIAGNOSIS. FOR TRACO, MANY OF YOU VISITED THE TUMOR BOARDS AND HEARD ABOUT CASE REPORTS. AND TODAY DR. OLAKU PRESENTS THE CASE REPORTS TO YOU. >> THANK YOU. THANK YOU AND FOR STAYING BEHIND. REALLY APPRECIATE IT. WE TALK ABOUT CASE REPORTS. SO WHAT I HOPE TO ACHIEVE DURING THIS LECTURE IS TO DESCRIBE THE HISTORY OF CASE REPORTS, RECOGNIZE THE POTENTIAL ROLES OF CASE REPORTS, DESCRIBE CASE REPORTS, OUTLINE PERTINENT INFORMATION FOR A GOOD CASE REPORT. CASE REPORT IS DEFINED, ONE DEFINITION IS A FORMAL SUMMARY OF A UNIQUE PATIENT AND HIS OR HER ILLNESS, INCLUDING THE PRESENTING SIGNS AND SYMPTOMS, DIAGNOSTIC STUDIES, TREATMENT COURSE AND OUTCOME. CASE REPORTS PROBABLY STARTED THE OLDEST EXAMPLE IS PROBABLY THE MEDICAL LITERATURE, CLINICAL CASES FROM EGYPTIAN ANTIQUITY PAPEROUS. THAT WAS THOUGHT TO BE AROUND 1600BC. SOME PEOPLE THINK THAT THEY WERE PROBABLY REWRITTEN FOR EXAMPLE SOME CENTURIES BEFORE THAT TIME. AMONG THESE WERE 48 CASES DISCUSSING INJURIES OR DISORDERS OF THE HEAD AND UPPER TOURS TORSO. CASE REPORTS ARE USUALLY DESCRIBED USING THE SENT FLEECE WHICH THEY WERE WRITTEN OR BY THE -- CENTURIES IN WHICH THEY WERE WRITTEN OR THE MAIN ACTORS INVOLVED IN THE WRITING OF THE CASE REPORTS. SO FOR EXAMPLE WE HAVE WHAT IS CALLED THE HIPPOCRATIC CASE REPORTS. AND THIS EMPHASIZE ACCURATE DESCRIPTIONS OF ONLY CLINICALLY RELEVANT FINDINGS. AND BOTH OF PHYSICAL AND MENTAL FINDINGS WERE DESCRIBED AND THE COMPLAINTS WAS FOR THE MOST PART ABSENT. THEN YOU HAVE WHAT KEY CALL THE GAELIC CASE REPORTS. GAL EN DESCRIBED HIS WORKING DAY, HIS DOUBTS AND WOULD DIAGNOSIS AND HIS INTERACTIONS WITH THE OTHER PHYSICIANS AS THE DISEASE UNFOLDS. SOME PEOPLE BELIEVE THAT IN THE MIDDLE AGES, THE WESTERN WORLD WAS DOMINANT. HOWEVER THERE WAS INCREASE A LOT OF INFORMATION COMING FROM ISLAMIC MEDICINE. AND THOSE CASE REPORTS WERE SIMILAR TO BOTH THE HYPOCRITIC AND THE GAL INIC CASE REPORTS. AND MOST OF THOSE CASE REPORTS ADHERE TO THE GAIL ENIC IDEA OF HAVING A CONVERSATIONAL TONE BUT ALSO PUT MORE EMPHASIS ON PATIENTS SUBJECTIVE EXPERIENCES. AT THE SAME TIME, PHYSICIANS WERE DRAMATIC IN THE WAY THEY WROTE CASE REPORTS AND FOR EXAMPLE, IN THE CASE REPORT THAT APPEARED IN THE PHILOSOPHICAL TRANSACTIONS IN 1739, SAYING A GIRL THREE YEARS OLD WHO REMAINED A QUARTER OF AN HOUR UNDER WATER WITHOUT DROWNING. IN THE 19 CENTURY, CASE REPORTS DEALED LESS WITH OBJECTIVE ACCOUNTS OF THEIR ILLNESSES AND MORE TECHNICAL TERMS WERE INTRODUCED INTO THE CASE REPORTS. THERE WERE MORE ORGANIZED AND HAVING SECTIONS LIKE DEMOGRAPHIC DETAILS OF THE PATIENCE AND OUTLINE OF CLINICAL COURSE OF EVENTS. AT THE SAME TIME, MEDICAL TERMINOLOGY BECAME MORE PROMINENT. SIMILARLY, LOOKING AT CANCER PATIENTS, THE HISTORY WAS PRETTY MUCH THE SAME AND IT WAS THE FIRST LINE OF EVIDENCE WHERE EVERYTHING BEGINS. SOME OF THE EARLIEST CASE REPORTS OF BREAST TUMORS WERE ALSO RECORDED IN THE ANCIENT EGYPTIAN MEDICINE. SO ONE OF THE POTENTIAL RULES OF CASE REPORTS ON CASE SERIES? ONE IS RECOGNITION AND DESCRIPTION OF NEW DISUSE N1999 THE WEST NILE ENCEPHALITIS WAS IDENTIFIED IN NEW YORK CITY AS A NEW CASE IN THE UNITED STATES. ANOTHER POSSIBLE ROLE IS DETECTION OF DRUG SIDE EFFECTS. MOST DRUG RETRACTIONS USUALLY FOLLOW CASE REPORTS. ON THE OTHER HAND, THEY ARE ALSO ADVANTAGES OF BENEFICIAL THINGS THAT CAN COME OUT OF CASE REPORTS. FOR EXAMPLE, SILL DENNA FILL WAS DESIGNED AS A DRUG TO TREAT HYPERTENSION. HOWEVER, IN THE COURSE OF THE TRIAL THEY FIND OUT THAT A BENEFICIAL SIDE EFFECT WAS PICKED UP, WHICH NOW BECOMES WHICH IS NOW BENEFITING A LOT OF PEOPLE. THE TREATMENT IS VIAGRA. BUT IT WAS DISCOVERED ACCIDENTLY. IN THE SAME VAIN, YOU HAVE ANTI-DEPRESSANT DRUGS THAT WERE FOUND TO BE USEFUL FOR PATIENTS WHO ARE UNDERGOING SMOKING CESSATION BECAUSE THEY WERE FINDING A LINK BETWEEN SMOKING CESSATION AND DEPRESSION. SO ANTI-DEPRESSANT DRUGS WERE PRESCRIBED FOR THOSE PATIENTS. CASE REPORTS ALSO CAN BE USEFUL IN STUDY OFFED MECHANISM OF DISEASE, FOR EXAMPLE INHERITED DIABETES ASSOCIATED WITH DEAFNESS. THIS WAS DISCOVERED BY LOOKING AT FAMILY HISTORY OF PEOPLE AND WAS ABLE TO IDENTIFY THIS DISEASE AND THEN FROM THERE ONWARDS ABLE TO GET AND IDENTIFY THE MECHANISM. CASE REPORTS CAN BE VERY USEFUL IN MEDICAL EDUCATION AND AUDIT T IS ALSO USEFUL IN THE RECOGNITION OF RARE MANIFESTATION OF DISEASES. AND IT CAN HAVE IMPACT ON HEALTH POLICY. FOR EXAMPLE, RECENTLY ZIKA VIRUS OR A FEW YEARS AGO WITH THE EBOLA VIRUS WHERE POLICIES HAD TO BE MADE AS A RESULT OF THE CASES THAT CAME INTO THE UNITED STATES. SO CASE REPORTS CAN BE USED IN DESCRIBING NEW DISEASE OR DIAGNOSIS. HISTORIC CASE REPORTS SHOWS COMMUNICATION BETWEEN PHYSICIANS AND THAT ULTIMATELY BECAME THE ORIGIN OF JOURNALS. HYPOCRITE ACHES - DESCRIBED CASE REPORTS OF MELANOMA AND IN 1832, 6 CASES WERE DESCRIBED, TWO OF WHICH WE NOW KNOW AS HODGKIN'S DISEASE. SIMILARLY IN 1957, IT WAS DESCRIBED TUMOR IN THE JAW OR ANGLE OF THE JAW OF THE AFRICAN CHILDREN ALSO CALLED BURKITT'S LYMPHOMA TODAY AND IN 1990, FAR SET AND COLLEAGUES DESCRIBED TWO PATIENTS WITH A NEW TYPE OF LYMPHOMA CALLED HEPATOSPLENIC T-CELL LYMPHOMA LEADING TO MORE FOCUSED RESEARCH. SO WE ARE GOING TO DESCRIBE SOME CASE REPORTS TO YOU. THIS IS A CASE OF A YOUNG FEMALE ATHLETE ACUTE LOW BACK PAIN CAUSED BY STAGE 4 BREAST CANCER. 27-YEAR-OLD LADY THAT PRESENTED TO THE OFFICE OF THE CHIROPRACTOR WITH THE CHIEF COMPLAINT OF LOWER BACK PAIN AFTER WARMING UP AND PARTICIPATING IN KICK BALL MATCH. SHE REPORTED FEELING DISCOMFORT WHILE JOGGING AND SUBSEQUENTLY HAVING PAIN AFTER STRIKING THE BALL WITH HER RIGHT FOOD. THE PAIN WAS MAINLY ON THE L2L3 LEVEL WITH MILD RADIATION INTO THE RIGHT PARAVERTEBRAL REGION. SHE DESCRIBED THIS PAIN AS CONSTANT AND SHARP AND STABBING BUT NO RADIATION OF THE PAIN INTO THE EXTREMITIES. SHE HAD A PAST HISTORY OF UNCOMPLICATED LOW BACK PAIN DURING HER TEENAGED YEARS THAT WAS TREATED CONSERVATIVELY AND ATTRIBUTED TO LUMBAR SCOLIOSIS. ON PHYSICAL EXAMINATION THERE WAS DECREASE INFLECTION AND EXTENSION ACTIVE RANGE OF MOTION WITH PAIN IN THE UPPER LUMBAR AREA AND TENDERNESS ON PALPATION. THE PATEL AR AND AKELIES TENDON REFLEXES WERE 2-4 ANDBA BIN SKI AND LOWER EXTREMITY CLONE US WERE ABSENT BILATTERLY. THE MUSSEL TESTING WAS SIMILAR ON BOTH SIDES AND AROUND THE PARASPINAL MUSCLE THERE WAS INCREASED TONE AT THE LEVEL OF THE COMPLAINT. THERE WAS A POSITIVE FAMILY HISTORY OF BREAST CANCER IN THE PATIENT'S AUNT AND GRANDMOTHER. AND IN PREVIOUS YEARS SRI HAD ROUTINE MAMMOGRAMS TO OBSERVE A ASSIST INERER RIGHT BREAST. - COOL SIFT IN HER RIGHT BREAST. SO DIAGNOSIS OF LUMBAR SPRAIN AND STRAIN WAS MADE AND RADIOGRAPHS OBTAINED TO RULE OUT SPONDILOLYSIS. WHEN THEY LOOKED BACK RETROSPECTIVELY, THEY FOUND THERE WERE SUBTLE LOU SENSIES VISIBLE IN THE VERTEBRAL BODY AND LEFT PED I KEL THEY MISSED INITIALLY. YOU CAN SEE IT SLIGHTLY LUCENT HERE AND AROUND HERE. SAME THING HERE. SO THEY TREATED HER WITH SOFT TISSUE MOBILIZATION TO LUMBAR AND HIP AND SHE WAS PLACED ON CONSERVATIVE TREATMENT PLAN FOR TWO WEEKS. HER EMPLOYER'S PHYSICIAN PRESCRIBED ORAL ANTI-INFLAMMATORY DRUGS AND PHYSICAL THERAPY WHICH SHE HAD TO STRENGTHEN THE CORE MUSCULATURE AND INCREASE THE RANGE OF MOTION. TWO WEEKS AFTER SHE RETURNED TO CHIROPRACTIC OFFICE BECAUSE THE SIGNS AND SYMPTOMS DID NOT CHANGE AND AN MRI SCAN REVEALED A 2.2 CENTIMETER EXPANSIBLE LESION IN THE LEFT L2 VERTEBRAL BODY. AND THERE WERE DIAGNOSIS OF OSTEOBLASTOMA, GIANT CELL TUMOR, METASTATIC DISEASE OF UNKNOWN ORIGIN WAS MADE. YOU CAN SEE HERE AND HERE THE TUMOR. YOU CAN SEE SPREADING TO THE PED GEL. SO SHE WAS REFERRED TO ONCOLOGIST WHO MADE DIAGNOSIS OF STAGE 4 DISEASE BREAST CANCER. SHE HAD ULTRASOUND AND MAMMOGRAM GUIDED THAT REVEALED THE CAPSEROUS TUMOR IN THE RIGHT BREAST. TWO MORE METASTATIC LESIONS WERE DISCOVERED AT THE CICS AND C7 SPINAL LEVELS VIA BONE SCAN AND MRI. THE TUMOR WAS HOMORECEPTOR POSITIVE AND HER 2 NEGATIVE. THE ORIGINAL ASSIST WAS SIFT WAS FOUND TO BE BENIGN. IT WAS BELOW THE SIFT THEY WERE TREATING OVER THE YEARS. SHE HAD A RIGHT LUMPECT HE AND LYMPH NODE REMOVAL IN 2016. THE SPINAL LESIONS DIMINISHED HOWEVER METASTATIC LESION CONFINED TO THE LIVER. THIS YEAR SHE BEGAN A TRIAL OF XELODA AND SHE IS CURRENTLY ACTIVE IN EXERCISE AND PARTICIPATE IN WEIGHT TRAINING AND BOWLING. THIS IS A CASE OF A LADY WHO HAS SQUAMOUS CELL CARCINOMA OF THE TONGUE DURING PREGNANCY. SHE HAD TWO CHILDREN AND REFERRED AT 14 WEEKS GESTATION TO THE ORAL MAX FACIAL SURGERY SERVICE WITH BIOPSY PROVEN POORLY DIFFERENTIATED SQUAMOUS CELL CARCINOMA WITH PERINEURAL INVASION OF THE RIGHT TONGUE IN AN AREA OF -- SHE DOESN'T HAVE A HISTORY OF SMOKING AND SHE CONSUMED ALCOHOL OCCASIONALLY BEFORE HER PREGNANCY. SO THAT IS THE AREA THAT WAS THE LESION THAT SHE HAD ON THE TONGUE. MRI IMAGING DEPICTED END PHYTIC MASK OF THE RIGHT TONGUE APPROACHES THE MID LINE AND THE MUSCLE ON THE RIGHT-HAND SIDE WAS INVOLVED WITH PROMINENT IPSILATERAL LEVEL 2A LYMPH NODE WAS NOTED. SO CLINICAL AND RADIOLOGICAL DIAGNOSIS, DIAGNOSED AS T4AN1MX. AND THAT'S THE MRI. YOU CAN SEE THE TUMOR THERE. THEY DISCUSSED THE MANAGEMENT OPTION. THE PATIENT WANTED TO CONTINUE HER PREGNANCY AND AT 16 WEEKS GESTATION SHE UNDERWENT A RIGHT EM I GLOSSECTOMY AND BILATERAL LEVEL BARACK OBAMA KNOW 1 TO 4 NECK DISSSECTION AND RADIAL FOREARM FREE-FLAP RECONSTRUCTION AND TRACHOSTOMY. THIS WAS THE EXCISED PART OF THE TONGUE AND THIS IS WHAT IT LOOKS LIKE AFTER THEY REPAIRED USING THE FLAP. SO SHE HAD A NECK DISECTION ON THE OPPOSITE SIDE BECAUSE THE MALIGNANCY WAS INCREASING THE MID LINE OF THE TONGUE. SHE HAD INFECTION THAT WAS TREATED POSTOPERATIVELY. AND PATHOLOGY REPORT REVEALED THE MARGINS OF THE MASS WAS NEGATIVE FOR CARCINOMA. HOWEVER, TWO LYMPH NODES WERE FOUND TO BE POSITIVE FOR REGIONAL METASTASES WITH EXTRA CAPSULAR SPREAD AT THE IPSILATERAL LEVEL 4 AND THE OTHER SIDE LEVEL ONE. SO THEY HAD TO CHANGE THE STAGING OF THE DISEASE. THIS IS HISATOLOGY THEY SHOWS YOU BREAKING OF THE CAPS LA AND THE TUMOR FROM THE LYMPH NODE. SO AFTER DISCUSSION WITH THE MATERNAL AND FEELS RISKS, SHE HAD ANGEVANT THEY WEREO POSTOPERATIVE DAY 25. SHE HAD RECEIVED 60 GRAY TO THE OPERATIVE BED AND 66 GRAY TO SITES OF REGIONAL METAFT AND HAD WEEKLY CARBOPLATIN. SHE HAD ADJUVANT THERAPY COMPLETED 16 WEEKS OF GESTATION AND THE ESTIMATED FETAL DOSE WAS 7 CENTER GRAY OF RADIATION. SHE HAD SERIAL ULTRASOUNDS SCAN PERFORMED TO EVALUATE THE FETAL GROWTH AND THIS IS JUST A PICTURE OF THE LADY SHOWING HOW SHE WAS TREATED WITH RADIATION. THE ULTRASOUND DEPICTED APPROPRIATELY GROWN FETUS MEASURING 92th PERCENTILE 23 WEEKS GESTATION BUT DROPPED TO 36th PERCENTILE AT 31 AND 37 WEEKS. SHE HAD A LIVE BORN MALE INFANT DELIVERED VAGINALLY AT 39 WEEKS. ONE YEAR AFTER MOTHER AND CHILD ARE DOING WELL WITH NO EVIDENCE OF REOCCURRENCE. SO THIS JUST SHOWS THE GROWTH OVER THE PERIOD OF THE PREGNANCY. THIS IS THE CASE OF 18 MONTH-OLD GIRL AS WITH A SMALL SUBCUTANEOUS LUMP OF THE ABDOMINAL WALL IN HER RIGHT HYPOQUANDARYIAC REGION. THE TUMOR WAS CONNECTED TO A SKIN AND HISTOLOGY CONFIRMED YOKE SACK TUMOR SHOWING MICROCYSTIC RETICULAR PATTERN WITH POSITIVE STAINING FOR CYTOKERATIN 8 AS WELL AS CYTOPLASMIC GRANULAR STAINING OF AFP. DURING SURGERY, THEY WERE NOT CLEAR OF TISSUE AND SHE WAS STAGE II ACCORDING TO PEDIATRIC ONCOLOGY GROUP. IT WAS 57 NORMAL T IS USUALLY LESS THAN 10 NANOGRAMS PER MILL. 3 WEEKS AFTER RESECTION AND DROPPED TO 15 NANOGRAM PER MILL ONE MONTH LATER. THE BETA SUB UNIT WAS NORMAL. MRI OF THE ABDOMEN WAS NORMAL. SHE WAS FOLLOWED UP. ONE YEAR LATER. MRI OF THE HEAD, NECK, THORAX AND ABDOMEN DID NOT SHOW ANY MASSES. SHE AT THIS TIME HAD A WIDE EXCISION OF THE LESION THAT CONFIRMED DYES DIAGNOSIS BY PATHOLOGY. SO THAT IS THE LESION THERE. YOU CAN SEE THE MEASUREMENT HERE ON MRI. SO THIS JUST GIVES A GRAPHIC REPRESENTATION OF THE MEASURING OF THE PROTEIN BEFORE IT CAME BACK TO NORMAL. SO FIVE YEARS SHE IS FINE. TUMOR-FREE WITHOUT ANY REMISSION. THIS IS A CASE OF NEVOL MAB HYPERINDUCED NYE RODE. A 60-YEAR-OLD MALE PATIENT PRESENTED WITH A SOFT TISSUE EDEMA IN THE RIGHT CERVICAL REGION IN 2014. HAD A HISTORY OF 86 PACK YEARS AND WAS A SOCIAL ALCOHOL CONSUMER. THIS T SCAN IDENTIFIED A TWO HADN'T 6 CENTIMETER MASS IN THE UPPER LOBE OF THE LUNG ALONG WITH ABNORMALLY ENLARGED N2 LYMPH NODES WITHOUT FURTHER EVIDENCE OF METASTASES. PATIENT HAD CONCURRENT CHEMO RADIO THERAPY WITH SIS PLAT IN AND RADIATION. IS THAT RESPONSE ACCORDING TO THE RESIST CRITERIA AND SURVEILLANCE CT IN MAY 2016 SHOWED PROGRESSIVE DISEASE WITH ENLARGEMENT OF TUMOR AND MEDIA STUNAL LIMPA DEANOPATHY. SO THE SECOND LINE OF CHEMOTHERAPY THAT INCLUDED INTRAVENOUS ENOUGH OL UMAB. FOLLOWING THE CYCLE, PATIENT DEVELOPED DIZZINESS, GAIT INSTABILITIY AND FATIGUE AND ANOREXIA WITHDRAWAL AND PEEODIC CONFUSION AND REDUCED ALERTNESS. PHYSICAL EXAMINATION DISCLOSED EDEMAD AND BRADY CARDIA WITH NO FOCAL NEUROLOGICAL OR OTHER ORGAN DEFICITS. AS A RESULT OF THE WORSENING SYMPTOMS,ES THEY HAD TO REQUEST A SERUM THYROID FUNCTION TEST THAT SHOWS TSH LEVEL WAS PRETTY HIGH AND THE FREE T4 LEVELS WERE LOW. SO HYPOTHYROIDISM WAS MADE PROBABLY DUE TO THE IN THIS VOL MAB SO THEY PROVIDE TO HER -- AND DIGS CONTINUED NEVOL MAB. DESPITE ALL THE TREATMENT, PATIENT CONTINUED TO EXPERIENCE FATIGUE, LOSS OF APPETITE, JOINT STIFFNESS AND NAUSEA AND PERIODIC ABDOMINAL PAIN. ON EXAMINATION, PATIENT WAS HYPERTENSIVE, DEHYDRATED AND HAD SKIN EXFOLATED DERMATITIS. ALL THOSE SYMPTOMS WERE COMPATIBLE WITH ADRENAL CORTICAL INSUFFICIENCY WITH FURTHER HORMONAL INFORMATION CONFIRMING THAT. THE ACTH LEVEL WAS LOW, 1.4. ALL OTHER BIOCHEMAL AND HEME TA LOGICAL SERUM EXAMINATIONS WERE NORMAL. MRI WAS NORMAL AND THERE WAS NO METASTASIS OR IMPROVEMENT OF THE PITUITARY GLAND. SO THIS IS THE MRI OF THE BRAIN THAT WAS NORMAL. SO THE RESULTS CONFIRMED CLINICALLY SUSPECTED ADRENAL INSUFFICIENCY THAT WAS MOST LIKELY SELECTIVE AND WAS INDUCED BY THE ANTI-PD-1 BLOCKADE. THE LH AND THE FSH LEVELS WERE NORMAL AND SHE WAS COMMENCED ON HOURLY HYDROCORTISONE IN ADDITION TO THE THYROXIN MEDICATION HE WAS TAKING. THERAPY RESULTED IN GRADUAL RESOLUTION OF ALL SYMPTOMS AND SIGNS RELATED TO HYPOTHYROID SKIMP ADRENAL FAILURE AND EXAMINATION IN MARCH 2017, THE PATIENT WAS ALERT, AFEEB RYLE WITH NORMAL BLOOD PRESSURE, GOOD APPETITE AND DISAPPEARANCE OF SKIN EXFOLIATION AND THE BLOOD LEVELS WERE WITHIN NORMAL RANGE. A CT SCAN OF HEAD AND NECK AND ABDOMEN PROGRAMMED IN APRIL OF THIS YEAR REVEALED STABLE DISEASE IN THE NECK AND LUNG AND MEDIA STEIN UM. THIS SHOWS YOU DIFFERENCES IN THE SKIN LESIONS BEFORE AND AFTER TREATMENT. AND THIS JUST GIVES YOU A GRAPHICAL REPRESENTATION OF THE HORMONE LEVELS AS HE WENT UP AND DOWN FOLLOWING TREATMENT. THIS IS A TABLE SHOWING CLINICAL AND LABORATORY EVOLUTION OVER TIME. SO WHEN I LOOK AT RARE CASES, IN RARE CASES, IT'S VERY DIFFICULT TO DO CLINICAL STUDIES AND THE ONLY EVIDENCE QUOTE/UNQUOTE THAT THE CLINICIAN WILL HAVE, MIGHT INFORM A RATIONAL APPROACH TO TREATING THE PATHOLOGICAL DISEASE. THIS IS A CASE OF A 15-YEAR-OLD GIRL BIVENTRICAL -- ADMITTED WITH SYMPTOMS OF CARDIORESPIRATORY DISTRESS AND SHE COMPLAINED OF SYMPTOMS OF CONGESTIVE HEART FAILURE FOR 20 DAYS. CLINICAL EXAMINATION SHOWED BLOOD PRESSURE TO BE NORMAL, TEMP NORMAL, SHE WAS BREATHING 24 BREATHS PER MINUTE AND HAD FACIAL EDEMA AND PALE. ON CHEST AUSCULLITATION, THE BREATH AND THE LUNGS HAD EVIDENCE OF FLUID IN THE CLONES THERE WAS PRO CORDIAL TREMBLE AND A MASSIVE MORE MER. OTHER FINDINGS INCLUDED ENLARGED LIVER, POSITIVE JUGULAR VEIN REFLUX AND EDEMA OF LOWER LIMBS. THE ALBUMIN LEVEL IS LOWER THAN NORMAL. THE END TERMINAL FRAGMENT WAS HIGH. CA125 WAS HIGH. CHEST X-RAY REVEALED CARDIACIAC DILATATION RIGHT LOWER PNEUMONIA PLEURAL EFFUCION. ECHO CARDIOGRAM REVEALED MULTIPLE CARDIAC MASS SYSTEM. ARISING FROM THE RIGHT VENTRICLE APEX AND PRO LAPSE THROUGH THE TRICUSPID VALVE INTO THE RIGHT ATRIUM DURING ASSISTLY. THAT'S THE ULTRASOUND SCAN SHOWING YOU THE MASS. AGAIN THE MULTIPLE MASSES ON ULTRASOUND SCAN. THE LEFT SEPTEMBER KEL WAS NOT DIALATED AND SHOWED NORMAL REFRACTION. MILD PER CARDIAL EFFUCION. THE FINDINGS WERE HIGHLY SUGGESTIVE OF MIXO MAS AND ALTHOUGH DIAGNOSIS OF VEGETATION OR THROMBOSE US COULD NOT BE EXCLUDED. SIZE OF LARGEST MASS, 5.5X3.8 CENTIMETERS. AGAIN YOU CAN SEE THIS SCAN. PET SCAN ALSO REVEALED THE TUMOR AND THE OXYGLUCOSE TEST DID ENHANCEMENT PATTERN OF BENIGN LESION AND LIKELY MUCUS TUMOR. NO OBVIOUS MALIGNANT LESION WAS IDENTIFIED DURING THE WORK UP. YOU CAN SEE THE PET SCAN LIGHTING UP BETWEEN THE TUMOR. SO SHE HAD SURGERY. A MASSIVE THROMBOSESIS WAS SEEN CLEARLY. A 60X45 MILLIMETER RED TUMOR WAS FOUND IN THE RIGHT VENTRICLE. IT HAD PRO LAPSED INTO THE RIGHT ATRIUM THROUGH THE TRICUSPID VALVE. THAT'S THE TUMOR THERE. EXAMINATION FOUND THE DIAGNOSIS OF MULTIPLE TUMORS AND DURING FOLLOW-UP, PATIENT WAS ASYMPTOMATIC AND HAD NORMAL BLOOD PRESSURE. NO SIGNS OF REOCCURRENCE OR INSUFFICIENCY. SO THAT IS WHAT WAS REMOVED. THAT'S JUST THE HISTOLOGY. THIS IS A CASE OF A 90-YEAR-OLD MAN LUNG CANCER WITH BLOOD IN THE STOOLS. HE HAD A HISTORY OF LEFT UPPER LOBE PULMONARY NODULE AND THAT PROGRESSIVELY BECAME WORSE OVER A MONTH PERIOD. HE HAD A PAST HISTORY OF SMOKING. AT THE TIME THEY SCOPED WAS ABOUT 10 YEARS PRIOR TO PRESENTATION. 5 MONTHS BEFORE, A 2.4 CENTIMETER LEFT UPPER LOBE PULMONARY NODULE WAS FOUND ON CHEST X-RAY. PARENT DECLINED ANY INVASIVE PROCEDURES. TWO MONTHS AFTER 8 MILLIMETER NODULES, SUSPICIOUS FOR METASTATIC LESIONS FOUND ON THE CT SCAN OF THE ABDOMEN AND PELVIS. PET SCAN CONFIRMED THE SAME THING. THAT'S WHAT THIS IS SHOWING. NODULES ON THE LIVER. THAT'S THE LUNG MASS AND THAT'S IT UP THERE. CT OF HEAD NEGATIVE FOR METASTASES. CLINICALLY STAGE 4 NEOPLASM. ALL THOSE THINGS POSITIVE FECALO CONSULT BLOOD TEST WAS POSITIVE. THEE HAD LOW HEMOGLOBE IN AND THE SCOPING WHEN THEY DID ENDOSCOPE, HAD NON OBSTRUCTING, NON BLEEDING GASTRIC ULCER WITH THE GREATER CURVAATURE OF THE GASTRIC BODY. THEY ALSO HAD A CLEAN BASE AND NO STIGMA OF BLEEDING AND NO EVIDENCE OF PERFORATION. BIOPSY CONFIRMED METASTATIC SQUAMOUS CARCINOMA INVOLVING THE BASE OF THE GASTRIC NEWICOSA WITHOUT SURFACE INVOLVEMENT. IT WAS REFERRED TO PALLIATIVE CARE AND UNFORTUNATELY 54 DAYS AFTER HE PASSED AWAY FROM GI BLEED. THAT'S THE HISTOLOGY. THIS IS A VERY AGAIN VARIETY OF CASES GIVING YOU INTERESTING. THIS IS A 64-YEAR-OLD MALE PATIENT THAT WAS ADMITTED TO HOSPITAL WITH PROGRESSIVE DYSPNEA AND COUGH. HE HAD UNDERGONE RIGHT LOBECTOMY OF LIVER CANCER IN 2006. 14 MONTHS AFTER CHEST CT SCAN REVEALED MULTIPLE METASTASES AND LEFT AGREEMENT GLAND METAFTIS. INVESTIGATION SHOWS THAT LIVER CANCER. PATIENT WAS PLACED ON PALLIATIVE CHEMOTHERAPY WITH 5FU ADD RIA MICE IN AND CARBOPLATIN AND PROGRESSED TO CHEMOTHERAPY. THEY INTRODUCED SECOND LINE TREATMENT AND THIRD LINE CHEMOTHERAPY OF THE DRUGS LISTED. THERE WAS NO RESPONSE. PATIENT WAS REFERRED TO A PALLIATIVE CARE FACILITY IN FEBRUARY OF 2009. HE HAD A PAST HISTORY OF PEP TITIS B VIRUS INFECTION. THIS IS JUST AN INVESTIGATION RESULT. THIS SHOWS NODULES IN THE LUNGS. SO THAT IS THE CHEST RADIOGRAPH SHOWING THE NODULES CT SCAN, ALL OVER. SO HE WAS SEEN EVERY THREE MONTHS IN PALLIATIVE CARE. HE CONTINUED TO HAVE COUGH AND DYSPNEA. NO CHANGES ON THE CHEST RADIOGRAPH. HOWEVER IN THE SECOND VISIT IN SEPTEMBER 2009, THE GENERAL CONDITION OF THE PATIENT IMPROVED AND THE COUGH AND DYSPNEA STOPPED AND THE CHEST RADIOGRAPH REVEALED THAT ALL METASTATIC NODULES DISAPPEARED. THIS IS CLEAR T HAD DROPPED WHOLE BODY PET SCAN IN DECEMBER 2009 REVEALED THAT ALL METASTATIC NODULES IN THE LUNGS AS WELL AS THE METASTATIC LESIONS OF THE TWO ADRENAL GLANCED AND LYMPH NODES DISAPPEARED. THE PATIENT SAID HE TAKEN SOME HERBAL MEDICINE FOR APPROXIMATELY ONE WEEK ON THE RECOMMENDATION OF HIS FAMILY. AND FOLLOW-UP CT SCAN DID NOT REVEAL RECURRENT METASTATIC DISEASE. AND AS IN MAY 2013, PATIENT WAS ALIVE WITHOUT ANY SYMPTOMS. IT JUST GIVES YOU AN IDEA OF SHOWING THE SCAN OR CHEST X-RAY WHERE THEY WERE AND WHEN THEY CLEARED UP AFTER THE CASE REPORT WAS PUBLISHED. THIS IS A DE NOVO HEPATOCELLULAR CARCINOMA POST-MULTIVISCERAL TRANSPLANTATION IN A CHILD. THE PATIENT WAS BORN PREMATURELY BECAUSE OF GASTROSISIS, THE ORGANS ARE PROTRUDING OUT OF THE ABDOMEN. BECAUSE OF THAT EXPOSURE, THEY HAD NECROSIS SO HAD TO REMOVE THE GUT. SO SHE HAD TO HAVE PARENTAL NUTRITION. AS A RESULT OF THAT, SHE DEVELOPED LIVER DISEASE THAT PROGRESSED TO CIRRHOSIS AND SEVERE PORTAL HYPERTENSION AND SUBSEQUENT DECOMPENSATION WITH COAG LOW PATHY. SHE HAD A TRANSPLANT LIVER, SMALL BOWEL, PANCREAS AND SPLEEN TRANSPLANTATION AT 8 MONTHS OF AGE. THE DISEASED DONOR WAS A 33-YEAR-OLD PREVIOUSLY HEALTHY FEMALE WITH NO PRIOR RELEVANT MEDICAL HISTORY AND THE CAUSE OF DEATH WAS HEAD TRAUMA. THE DONOR WAS NEGATIVE FOR HEPATITIS A, B, C HOWEVER, POSITIVE FOR EPSTEIN-BARR VIRUS IGG. THE HLA CROSS-MATCH WAS NEGATIVE. SO SURGERY WAS COMPLICATED BY COMP PARTMENT SYNDROME REQUIRING SPLEEN AFFECT ME. THE PATIENT RECEIVED DRUGS TO RECEIVE IMMUNOSUPPRESSIVE THERAPY. TWO MONTHS AFTER TRANSPLANT THEY DEVELOPED EBV VIREMIA REDUCED BY IMMUNOSUPPRESSION. AND THERE WAS REJECTION AGAIN INCREASED IMMUNOSUPPRESSION THERAPY AND THE EBV VIREMIA AND DEVELOPED POST TRANSPLANT LIMP NO PROLIFERATIVE DISEASE CONFIRMED BY A BIOPSY OF LYMPH NODES. CONDITION IMPROVED AFTER DOSE OF TACK ROW LIMB US WAS REDUCED AND RITUXIMAB WAS ADMINISTERED. SHE HAD INTESTINAL GRAFT DYSFUNCTION THAT LEAD TO 8ILE SCOPIES AND BIOPSIES AT 4 MONTHS. AT 3 YEARS OF AGE SHE WAS FOUND TO HAVE A MULTIFOCAL POST TRANSPLANT EBV ASSOCIATED SMOOTH MUSSEL TUMOR. IN THE SMALL BOWEL AND MESS ENTRY CONFIRMED BY BIOPSY. THE TUMORS WERE NOT RESPONSIVE TO CHEMOTHERAPY, RADIATION OR SURGICAL RESECTION. SHE WAS ENROLLED IN A CLINICAL TRIAL AT MEMORIAL SLOAN-KETTERING IN NEW YORK AND RECEIVED SEVERAL CYCLES OF GENETICALLY MODIFIED EBV-SPECIFIC CYTOTOXIC T LYMPHOCYTES IN ADDITION TO VORINOSTAT AS PART OF THE RESEARCH PROTOCOL. SHE WAS CLINICALLY STABLE, HOWEVER THE EBV ASSOCIATE THE TUMOR WAS PROGRESSIVE.& SHE REMAINED AT HOME WITHOUT ANY NEED FOR FREQUENT HOSPITALIZATION FOR 4 YEARS. SIX YEARS AFTER TRANSPLANTATION, ROUTINE SCAN SHOWED THAT THERE WAS TUMOR, HYPERVASCULAR MASS IN THE PATIENT'S LIVER. MRI IDENTIFIED HETEROGENEOUS LEFT DOMINANT HEPATIC TUMOR WITH MULTIPLE HYPERVASCULAR FOCI UNCHANGED FROM THE PRIOR CT. CLINICALLY, THE PATIENT WAS WELL AND STABLE HOWEVER THE LIVER LESION INCREASED IN SIZE. BIOPSY CONFIRMED HEPATOCELLULAR CORS GNOMA AND THE PATIENT UNDERWENT A LEFT HEPATIC LOBECTOMY WITH CLEAR RESECTION MARGINS. THERE WAS RESIDUAL NODULES RANGEES FROM .3 TO 1.5 CENTIMETERS. THAT'S THE RESECTED TUMOR THERE AND SOME OF THE HISTOLOY. AND THE STUDY THAT WAS DONE -- STAINING THAT WAS DONE. UNEVENT FULL, DISCHARGED 11 DAYS AFTER. STABLE FOR SEVERAL MONTHS, AND THEN MRI REVEALED THAT THERE ARE MULTIPLE NODULES IN THE LIVER AND OPERATIVE LEVEL HAD GONE UP. FINDINGS CONSISTENT WITH THE RECURRENT DISEASE PATIENT'S FAMILY DECIDED TO PRO WITH COMFORT CARE AND THE PARENT PASSED AWAY SIX MONTHS AFTER. SO OUR CASE REPORTS ARE IMPORTANT IN THIS ERA OF EVIDENCE-BASED MEDICINE. SOME PEOPLE BELIEVE THAT CASE REPORTS SHOULD BE ELIMINATED. THAT DOESN'T CONTRIBUTE MUCH TO SCIENCE TO EVIDENCE. HOWEVER, CASE REPORTS CANNOT PROVIDE EVIDENCE OF EFFICACY OR SAFETY IN THE DIAGNOSIS AND TREATMENT OF A DISORDER. ALBRIGHT AND HIS COLLEAGUES DID A STUDY OF 100 PUBLISHED CASE REPORTS IN THE ARCHIVES OF DERM TOY. THEY HAD DONE PUBLICATION BY US IN SUPPORT OF POSITIVE RESULTS, EXAGGERATED CLAIMS OF EFFICACY AND SAFETY, INNERADEQUATE INFORMED CONCEPT REPORTING, UNDER REPORTING OF PATIENT-CENTERED OUTCOMES. OUR CHALLENGE FOR CASE REPORTS IS FROM A BUSINESS PERSPECTIVE, CASE REPORT ARE RAILROADY CITED AND FROM THAT THEY GENERALLY NEGATIVELY HAVE A NEGATIVE IMPACT ON THE IMPACT FACTOR. NEGATIVE IMPACT ON THE IMPACT FACTOR. AND THAT MAY BE SOME AS IMPORTANT AS THOSE TRYING TO ADVERTISE OR PEOPLE WHO WANT TO PUBLISH, PROBABLY WANT TO PUBLISH IN A JOURNAL THAT HAS HIGH IMPACT FACTOR WHICH WILL DRIVE WHERE PEOPLE WHO ARE ADVERTISING WILL SPEND THEIR DOLLARS TO ADVERTISE. WE ARE CONCERNED WITH FINDING THE BEST EVIDENCE FOR CLINICAL DECISIONS, FOR EXAMPLE, WHAT WE APPLY TO A PARTICULAR THERAPY OR A DIAGNOSTIC TEST TO A PARTICULAR PATIENT? RANDOMIZED CLINICAL TRIAL SERVES VERY GOOD PURPOSE, THE FINAL EVALUATION OF THERAPIES OR TEST ESPECIALLY WHEN THEIR CLINICAL VALUE IS NOT IMMEDIATELY CLEAR-CUT. HOWEVER, CASE REPORTS HAVE OTHERS THAT ARE EQUALLY IMPORTANT IN THE PROGRESS OF MEDICAL SCIENCE AND EDUCATION. SO WE LOOK AT METANALYSIS OR SYSTEMIC REVIEWS ON CASE SERIES. REREACHED FROM THE LITERATURE OF THAT MOCKS FINN-RELATED OCULAR TOXICITY IN BREAST CANCER PATIENTS. THEY HAD A CLEAR PICTURE OF THE NATURE AND DISTRIBUTION OF THE TOXICITY AND THE SER SAFETY OF THE OCULAR FINDINGS. HOWEVER, THEY ALSO RECOGNIZED IT WAS DIFFICULT TO ATTRIBUTE THE OCULAR FINDINGS TO TAMOXIFEN AND OTHER COMPETING CAUSES OF RETINAL, AND MACULAR OR CORNUAL ABNORMALITIES. POST CASE REPORTS ON CASE SERIES OF PRIMARY CARCINOMA OF THE FALLOPIAN TUBE. AS A RESULT OF THIS THEY WERE ABLE TO OUTLINE MORE APPROPRIATE PATIENT CHARACTERISTICS AND THEY WERE ABLE TO HYPOTHESIZED ON THE UNDERDIAGNOSIS OF CASES, WHAT ARE THE CAUSES OF TREATMENT FAILURE, AND AT THE TIME THEY DID A STUDY WITH A LACK OF CONTROLLED TRIALS AND USEFULNESS OF A SECOND LOOK LAP ROT ME FOR MONITORING DISEASE RESPONSE TO THE TREATMENT GIVEN. WE LOOKED AT CASE REPORTS OF THERAPY USED BY CANCER PATIENTS. REPORTS WITH ANTI--TUMOR EFFECT AND 21 CASE REPORTS OF TOXIC EFFECT WERE IDENTIFIED. WE FOUND THERE WERE CLINICAL TRIALS CANCER POPULATIONS IN CERTAIN HERBS LIKE GREEN TEA, PHYTOESTROGENS, MISTLETOE, BEGANO DERMA, LOU SID YUM, NO ONEY AND SILLY MA RIN. AND ALSO STUDIES OF -- SAW PALMETTO AND MANY OF THE FINDINGS HAVE EITHER NOT BEEN EXPLORED OR THE RESULTS WERE NOT REPORTED IN ENGLISH. SO WE FOUND THAT FROM THESE CASE REPORTS, ONLY THE CHARACTERISTICS AND THE CASE OUTCOMES CAN BE ASSESSED THAT THE LEVEL OF CLINICAL RESEARCH. HOWEVER, IN SITUATIONS WHERE THERE IS NO OTHER ADEQUATE EVIDENCE, THE BEST OF THE FIRST LINE OF EVIDENCE MUST BE TAKEEN INTO ACCOUNT. WHAT IMPACT HAS CASE REPORT HAD IN MEDICAL RESEARCH? THE ONLY THING I WANTED TO FOCUS ON HERE IS THAT CASE REPORTS ARE FOLLOWED BY PUBLISHED TRIALS, ONLY 17% AND 83% DIDN'T HAVE ANY TRIALS. AND THE WAY YOU LOOK AT CASE SERIES THE SAME THING. WE FIND THE SAME THING. 31% WERE FOLLOWED BY PUBLISHED TRIALS AND MANY WERE NOT. JUST BECAUSE IT'S JUST MAYBE BECAUSE CASE SERIES ARE NOT JUST CASE REPORTS. SO HOW DO YOU WRITE A GOOD CASE REPORT? THE CARE GUIDELINES, THIS IS CASE REPORT GUIDELINES SOME VERY SMART PEOPLE CAME UP WITH SOME GUIDELINES IN 2013. THESE ARE RECOMMENDATIONS ON OR GUIDELINES THAT A GOOD CASE IS WHERE YOU HAVE A TITLE, KEYWORDS , ABSTRACT, INTRODUCTION, PATIENT INFORMATION, CLINICAL FINDINGS, TIMELINE, DIAGNOSTIC ASSESSMENT, THERAPEUTICS INTERVENTION. FOLLOW-UP ON OUTCOMES AND DISCUSSION AND PATIENT PERSPECTIVE AND INFORMED CONSENT. SO ONEFUL MY CONCLUSIONS CASE REPORT SHOULD BE WRITTEN IN ORGANIZED AND STRUCTURED MANNER. STILL VERY RELEVANT, I BELIEVE, IN TODAY'S MEDICINE. AND IN RARE INSTANCES WHERE CLINICAL TRIALS ARE NOT POSSIBLE FOR ETHICAL REASONS, CASE REPORTS OF SERIES MAY BE THE ONLY EVIDENCE AVAILABLE TO RECOMMEND TREATMENT. THANK YOU. [ APPLAUSE ] ANY QUESTIONS? >> FOR CASE REPORTS, ARE THEY MORE POPULAR IN ASIAN COUNTRIES? >> YES. THEY ARE MORE POPULAR. BUT IT'S GETTING BETTER NOW IN THE WESTERN PART OF THE WORLD. YOU NOW HAVE A SING BACK INTO GETTING MORE CASE REPORTS. EVEN SOME OF THE DISTINGUISHED JOURNALS ARE ALLOWING CASE REPORTS. MOST PEOPLE ARE AWARE OF THE NEW ENGLAND JOURNAL OF MEDICINE. EVERY WEEK THEY HAVE CASE REPORTS THEY DISCUSS EXTENSIVELY. SO YES, THERE SEEMS TO BE INTEREST BACK IN CASE REPORTS NOW.