>> THIS IS THE TRANSLATIONAL RESCORCH IN CLINICAL ONCOLOGY COURSE. WE'VE BEEN DOING THIS FOR 15 YEARS NOW. AND MY NAME IS TERRY MOODY, WITH THE NATIONAL CANCER INSTITUTE. AND SO THE BEST WAY TO GET ME IS THROUGH E-MAIL. WE HAVE AN ORGANIZING COMMITTEE FOR THIS CLASS, ONE OF THE PEOPLE ON THE COMMITTEE IS IRWIN ARIAS IN CHARGE OF DEMYSTIFYING MEDICINE, WHICH HAS A FORMAT SIMILAR TO THIS BUT DEMYSTIFYING MEDICINE FOCUSES ON ALL DISEASES, WHEREAS WE JUST FOCUS ON CANCER. WE HAVE LYUBA VARTKOVISKI, AND MY BOSS IS JONATHAN WIEST WHO PAYS FOR THE VIDEOCAST SO WE WANT TO BE NICE TO HIM. USUALLY THE CLASS IS AT 4:00 ON MONDAYS, BUT WE CAN'T ALWAYS GET THIS ROOM ON THAT PARTICULAR DATE. SUCH AS YESTERDAY WAS A HOLIDAY. SO WE'RE HAVING THE LECTURE ON TUESDAY TODAY. AND THEN NEXT WEEK WE GO BACK TO MONDAY AT FOUR TO SIX, AND THE CLASS IS VIDEOCAST AT THE NIH, VIDEOCAST.NIH.GOV, BEING VIDEOCAST LIVE NOW. AND SO AFTER TWO DAYS, IT'S THEN ARCHIVED, SO YOU CAN CALL IT UP ANYTIME ON YOUR COMPUTER IF YOU MISS A CLASS OR WANT TO SEE IT AGAIN, TWO DAYS AFTER THE LECTURE. IT'S ON YouTube ON THE NIH SITE. SO NEXT WEEK WE HAVE A LECTURE ON CLINICAL TRIALS AS WELL AS PRECISION MEDICINE, AND BASICALLY AT NIH WHAT THEY DO IN THE CLINIC NOW FOR THE CANCER PATIENTS IS THEY DO A MOLECULAR ANALYSIS OF THE TUMOR, WHEN THE PATIENT COMES IN, AND THEY PUT THE PATIENT ON THE CLINICAL TRIAL AND TREAT THEM WITH VARIOUS DRUGS, BASED ON THE GENOMIC PROFILE OF THE PATIENT THAT DICTATES WHAT THE THERAPY IS. AND THEN WHEN THE TRIAL IS COMPLETE, THEY ANALYZE THE TUMOR AGAIN FOR THE GENETIC PROFILE, TO SEE IF IT'S CHANGED. AND SOMETIMES IT DOES. CANCER, IT'S A MOVING TARGET, SO WE HAVE AN INITIAL DISEASE AND THE DISEASE MAY RESPOND TO A PARTICULAR THERAPY, BUT THEN DURING THE THERAPY THE CANCER CAN MUMU MUMU TATE FURTHER AND BECOME RESISTANT AND YOU HAVE TO FIND ALTERNATIVE THERAPY. IT KEEPS US BUSY. ON SEPTEMBER 18 WE DON'T HAVE A LECTURE BECAUSE WE COULDN'T GET THE ROOM BUT ON SEPTEMBER 25 WE HAVE IMMUNE CHECKPOINT INHIBITORS AND OVARIAN CANCER, AGAIN MONDAY AFTERNOON. ONE RAPIDLY DEVELOPING THERAPY IS ANTIBODIES, LIGANDS, PD1, MANY ARE IMMUNE TO THE RESPONSE, AND WHEN YOU TREAT THE CANCER WITH ANTIBODIES TO PD1, THEN THE CANCER IS EXPOSED. AND THE IMMUNE SYSTEM CAN RESPOND TO IT, AND STEPHANIE GOFF WAS ONE OF THE KEY CLINICIANS ON THE DISCOVERY CHANNEL RECENTLY, THEY PRESENTED A SERIES OF LECTURES ON FIRST RESPONSE OF IMMUNE PATIENTS. AND SHE FEATURED A PATIENT WHO HAD MELANOMA AND WHO WAS TREATED WITH THE IMMUNE CHECKPOINT INHIBITORS. SO THEN IN OCTOBER WE FOCUS ON OTHER TYPES OF CANCERS SUCH AS PROSTATE CANCER, AND THEN OCTOBER 9 IS A HOLIDAY, THE COLUMBUS DAY, SO WE GO BACK TO TUESDAY, OCTOBER 10. AND WE TALK ABOUT COMMON TYPES OF THERAPY FOR CANCER. THAT'S RADIATION ONCOLOGY, SOME CANCERS RESPOND TO THAT QUITE WELL. AND THEN THERE'S ALSO CHEMOTHERAPEUTIC AGENTS SUCH AS TOPOISOMERASE USED IN CHEMOTHERAPY. AND OCTOBER 17, AGAIN A TUESDAY, ONE OF THE PEOPLE LECTURING ON SMALL MOLECULES, AND MY SPECIALTY IS ACTUALLY LUNG CANCER, AND ONE OF THE KEY MUTATIONS IN NON-SMALL CELL LUNG CANCER IS THE EGF RECEPTOR, RECEPTOR TYROSINE KINASE. WHEN THIS GETS MUTATED, YOU CAN THEN TREATED WITH TYROSINE KINASE INHIBITORS, THESE ARE SMALL MOLECULES THEN THAT BLOCK THE ENZYMATIC ACTIVITY OF THE RECEPTOR TYROSINE KINASE, SO THEY ARE IN VOGUE. OCTOBER 23 WE GO BACK TO A MONDAY, AND TALK ABOUT BREAST CANCER, SO THE FOUR BIG KILLERS IN CANCER ARE BREAST CANCER, LUNG CANCER, PROSTATE CANCER AND COLON CANCER. THEN OCTOBER 30 WE HAVE A LECTURE ON CANCER HEALTH DISPARITIES, SO OFTENTIMES MINORITIES SUCH AS AFRICAN-AMERICANS HAVE A MUCH MORE DIFFICULT TIME RESPONDING TO CANCER THERAPIES, ESPECIALLY IN BREAST CANCER, MANY OF THE WOMEN HAVE TRIPLE-NEGATIVE BREAST CANCER AND IT'S VERY DIFFICULT TO FIND A THERAPY FOR THAT. AND THEN NOVEMBER 6 IT'S A MONDAY AGAIN, WE HAVE JOHN SCHILLER LECTURING ABOUT CERVICAL CANCER, AND ABOUT 1/3 OF THE CANCER THERAPIES COMMONLY USED WERE DEVELOPED HERE AT NIH. YOU START IN THE BASIC LAB, AND JOHN FOUND THAT L1 VIRUS-LKE PARTICLES PRODUCE A VERY GOOD IMMUNE RESPONSE AGAINST CERVICAL CANCER, AND SUBSEQUENTLY THAT'S BECOME A CERVICAL CANCER VACCINE, AND THE DRUG GARDASIL IS USED NOW IN TEENAGE GIRLS, ABOUT A THIRD OF THE GIRLS IN THIS COUNTRY GET VACCINATED WITH GARDASIL, AND THAT MAKES THEM RESISTANT TO GETTING THE VIRUS FOR CERVICAL CANCER. AND THEN WE GO BACK TO A TUESDAY, NOVEMBER 14, EVA SZABO TALKING ABOUT THE NON-SMALL CELL LUNG CANCER, AND NOVEMBER 20 WE FINALLY CLOSE OUT ON THE MONDAY, WE TALK ABOUT GENOMICS AND HIV. NOVEMBER 27 THERE'S A LECTURE ON EPIGENETICS, NOT ALL CANCERS ARE CAUSED BY GENOMES, AND WE CLOSE ON PANCREATIC AND NANOTECHNOLOGY. WE GO FOR 13 WEEKS, AND WE HAVE A WEBSITE, WHERE YOU CAN FIND THE LECTURES. WHAT WE TRY TO DO IS POST THE POWER POINTS, BUT TO DO THAT WE HAVE TO MAKE THEM 508 COMPLIANT, AND THAT TAKES A BIT OF TIME. SO MOST OF THE LECTURES WILL BE POSTED ULTIMATELY ON THE WEBSITE. AND THE WEBSITE IS ALSO WHERE THE FINAL EXAM WILL BE FOR THOSE OF YOU WHO WANT TO GET A CERTIFICATE, BASICALLY THERE'S A COMPUTER-GRADED FINAL EXAMINATION AFTER THE CLASS ENDS, AND THEN ANOTHER UNIQUE FEATURE OF THE TRACO IS IN DECEMBER WE ARRANGE SO THAT YOU CAN VISIT CORE FACILITIES, NCI HAS ONE IN PATHOLOGY THAT WE ROUTINELY VISIT, AND THEN ALTERNATIVELY YOU CAN VISIT TUMOR BOARDS, WHERE THE CASES ARE DISCUSSED FOR INDIVIDUAL PATIENTS THAT BE BEING TREATED ON CLINICAL PROTOCOLS. SO THAT MAKES IT DIFFERENT FROM AN ACADEMIC COURSE. WE ALSO ALLOW YOU TO SEE OUR CORE FACILITIES AND TUMOR BOARDS. SO ARE THERE ANY QUESTIONS ON THE ORGANIZATION OF THE COURSE? OKAY. IF NOT, THEN WE'LL PROCEED. AND DISCUSS THE FIRST LECTURE, AND SO WE MENTIONED BEFORE THE BIG FOUR KILLERS IN THE U.S. ARE LUNG CANCER, COLON CANCER, BREAST CANCER, AND PROSTATE CANCER. THESE COMBINED CONSTITUTE HALF OF ALL THE CANCER CASES IN THE U.S. WE SEE THERE'S A LITTLE OVER A MILLION CASES A YEAR. AND ABOUT HALF OF THESE PEOPLE WILL ULTIMATELY DIE FROM THE CANCER, BUT WE SEE SOME TYPES OF CANCERS HAVE A VERY GOOD THERAPEUTIC OUTCOME, BREAST CANCER WE HAVE MANY, MANY DRUGS THAT WE CAN USE TO TREAT IT. SO AS A RESULT ONLY ABOUT 20% OF THE PATIENTS THAT GET BREAST CANCER WILL ULTIMATELY DIE FROM IT. SO THAT'S VERY GOOD NEWS. PROSTATE CANCER ALSO WE HAVE LOTS OF DRUGS FOR IT. BUT BASICALLY PROSTATE CANCER GROWS VERY SLOWLY, AND A LOT OF MEN THAT ARE DIAGNOSED WITH PROSTATE CANCER ULTIMATELY THEY WILL DIE FROM OTHER THINGS SUCH AS HEART DISEASE AND NOT PROSTATE CANCER. IF THE PROSTATE CANCER IS GROWING VERY SLOW, THE CLINICIAN DOES NOTHING, BECAUSE THE PATIENT DOESN'T REALLY NEED DRUGS. AND WE SEE WITH COLON CANCER, AGAIN WE HAVE A PRETTY GOOD RESPONSE RATE, BUT ABOUT 30% WILL DIE FROM IT, AND COLON CANCER BASICALLY IS GENETIC. SO ABOUT 30% OF THE CASES IN COLON CANCER ARE GENETIC. AND IT'S VERY DIFFICULT TO TREAT THESE. WHEREAS IN BREAST CANCER, MAYBE 10% OF THE CASES ARE GENETIC, PROSTATE CANCER EVEN LESS, AND LUNG CANCER THERE'S VIRTUALLY NO CASES THAT ARE GENETIC. ALL THE CASES OF LUNG CANCER, MOST OF THEM COME FROM SMOKING CIGARETTES, AND WE SEE THE MORTALITY RATE IS VERY HIGH. ON THE ORDER OF 90%. SO LUNG CANCER WE STILL HAVE A VERY LONG WAYS TO GO, BUT THESE IMMUNE CHECKPOINT INHIBITORS ARE NOW STARTING TO SHOW SOME PROMISE IN LUNG CANCER, IN ABOUT 20% OF PATIENTS ARE NOW RESPONDING TO THESE IMMUNE CHECKPOINT INHIBITORS. SO IN THE LAST DECADE, WE'VE GOT THE TYROSINE KINASE INHIBITORS THAT RESPOND TO PATIENTS THAT HAVE EGF RECEPTOR MUTATIONS. AND NOW WE HAVE THE IMMUNE CHECKPOINT INHIBITORS, AND SOME OF THE PATIENTS RESPOND TO THAT. AND EVEN IF YOU ONLY HAVE 10% OF THE PATIENTS RESPONDING, YOU'RE SAVING 17,000 LIVES A YEAR. AND WITH THE IMMUNE CHECKPOINT INHIBITORS WE'RE GETTING ABOUT A 20% RESPONSE RATE, SO YOU'RE SAVING ABOUT 30,000 LIVES A YEAR. AND THAT'S A BIG NUMBER. SO WITH LUNG CANCER OVERALL WE HAVE A LITTLE OVER HALF A MILLION DYING EACH YEAR, BUT WE SEE THAT LUNG CANCER IS ACCOUNTING FOR A LOT OF THESE DEATHS. SO RIGHT NOW, WE SORT OF LEVELED OFF IN TERMS OF DEATH, AND THAT'S BECAUSE WE'RE GETTING MUCH BETTER AT TREATING BREAST CANCER, PROSTATE CANCER AND COLON CANCER, BUT THE ONLY WAY WE'RE GOING TO GO DOWN IN THESE DEATHS IS IF WE GET SOMETHING THAT'S REALLY EFFECTIVE FOR LUNG CANCER. SO I STARTED WORKING ON LUNG CANCER ABOUT 30 YEARS AGO. I KNEW IT WAS A LIFETIME CHALLENGE. IT'S STILL GOING TO BE A CHALLENGE FOR ALL OF YOU TO WORK IN THE FIELD. THERE'S STILL A LONG WAYS TO GO. OKAY. SO THAT'S THE BIG FOUR. AND THOSE ARE THE BIG KILLERS IN THE U.S. WE HAVE OTHER TYPES OF CANCERS THAT KILL 10,000 TO 30,000 ANNUALLY SUCH AS PANCREATIC CANCER. PANCREATIC CANCER, GLIOBLASTOMA, BRAIN CANCER, OVARIAN CANCER, AND LUNG CANCER, VERY DIFFICULT TO TREAT. ALMOST EVERYONE WHO GETS THAT IS LIKELY GOING TO DIE FROM IT. OTHER TYPES OF CANCER SUCH AS LEUKEMIA, WE HAVE FAIRLY GOOD TREATMENT FOR THAT NOW. STOMACH CANCER, IT'S NOT A BIG PROBLEM IN THE U.S., BUT IN ASIA STOMACH CANCER IS A BIG PROBLEM AND IT'S BECAUSE OF THE FOOD THAT THE PEOPLE ARE EATING. USUALLY THE FOOD IS POORLY PREPARED, AND OFTENTIMES IT'S SMOKED AND CURED IN SALT, AND THIS LEADS TO MANY CASES OF STOMACH CANCER IN ASIA. WE MENTIONED OVARIAN CANCER IS DIFFICULT TO TREAT, BRAIN CANCER. LIVER CANCER, IT CAN COME FROM ORGANIC SOLVENTS SUCH AS I'M A CHEMIST AND WORK IN THE LAB AND SOLVENTS LIKE COLOR FORM JUST DESTROY YOUR LIVER. YOU'RE SUPPOSED TO WEAR GLOVES AND NEVER LET COLOR FORM TOUCH YOUR SKIN. LIVER CANCER CAN BE CAUSED BY CIRRHOSIS OF THE LIVER IF YOU DRINK TOO MUCH ALCOHOL. AND THEN ANOTHER TYPE OF CANCER IS ESOPHAGEAL CANCER, AGAIN THIS IS ASSOCIATED WITH THE SMOKE OF THE CIGARETTES. SO, CANCER RISKS, ALCOHOL WE MENTIONED. IF YOU HAVE TOO MUCH ALCOHOL, THAT CAN LEAD TO LIVER CANCER. ASBESTOS, IN OLD BUILDINGS FOR INSULATION THEY USED MATERIALS THAT HAD ASBESTOS IN THEM. AS LONG AS THE ASBESTOS STAYS IN THE WALL, YOU'RE FINE. BUT IF PEOPLE START DOING CONSTRUCTION AND RIPPING UP THAT WALL, YOU BETTER GET OUT OF THAT ROOM. AND JUST TO SHOW YOU WHEN I WAS AN UNDERGRADUATE STUDENT, I USED TO WORK IN A CHEMICAL LAB. AND THIS CHEMICAL LAB, THEY MADE FILTER PADS MADE OF ASBESTOS. ALL THE WORKERS DOWN THERE, THEY WOULD JUST WORK, AND I WENT DOWN THERE ONCE AND I WORE A MASK. THEY ALL STARTED MAKING FUN OF ME. WHAT ARE YOU AFRAID OF? I SAID IT'S ASBESTOS. YOU'RE GOING TO GET MESS MESOTHELIOMA OF THE LUNG IF YOU BREATHE IT ALL THE TIME. HAVE YOU TO BE AWARE OF YOUR ENVIRONMENT. DIET, WE MENTIONED IN ASIA THEY EAT FOOD THAT'S POORLY PREPARED, THIS CAN LEAD TO STOMACH CANCER. THERE'S ALSO GENETIC COMPONENTS. WE MENTIONED COLON CANCER, ABOUT 30% OF THE CASES COME FROM GENETIC ABNORMALITIES, AND SO WITH COLON CANCER, ESPECIALLY, THEY KEEP PARENTAL TREE. DO YOUR PARENTS HAVE COLON CANCER? THEN YOU'RE AT HIGH RISK OF GETTING COLON CANCER. HAVE ESTRODIA, WHETHER IN 30%, AND PROSTATE CANCER IT'S ANDROJOKES. OBESITY INCREASES RISK OF COLON CANCER. IN OUR SOCIETY IN GENERAL, WE'RE BECOMING MORE AND MORE OBESE. SO YOU HAVE TO WATCH YOUR DIET. IONIC RADIATIO SUCH AS ATOMIC BOMB. WHEN ATOMIC BOMB WAS DROPPED ON JAPAN AT THE END OF WORLD WAR II PATIENTS INITIALLY GOT LEUKEMIA AND THEY DIED, AND THE ONES THAT DIDN'T GET LEUKEMIA, A LOT OF THEM TEN YEARS LATER STARTED GETTING BREAST CANCER, AND THEY DIED. TOBACCO WE MENTIONED, 80% OF THE LUNG CANCER CASES RESULT BECAUSE THE PEOPLE SMOKE CIGARETTES. UV RADIATION, IN FLORIDA AND ESPECIALLY ARIZONA, THE SUN APPEARS TO BE GETTING STRONGER AND STRONGER, BECAUSE WE'RE DEPLETING THE OZONE IN THE ENVIRONMENT. SO MORE UV RAYS GO THROUGH, AND YOU HAVE TO PROTECT YOUR SKIN WITH SUNSCREEN OR ELSE YOU CAN GET MELANOMA. AND THEN VIRUSES. WE MENTIONED CERVICAL CANCER. IT'S A VIRAL COMPONENT. SO MY SPECIALTY IS LUNG CANCER. AND WITH LNG CANCER, OVER 150,000 PEOPLE GET IT ANNUALLY. AND THERE'S 45 MILLION CURRENT SMOKERS, BUT THE GOOD NEWS IS THERE'S 45 MILLION EX-SMOKERS. AND SO WHEN YOU STOP SMOKING, YOUR RISK OF LUNG CANCER SLOWLY GOES DOWN. IT TAKES ABOUT TEN YEARS TO GET BACK DOWN TO NORMAL RISK. WHEREAS IF YOU STOPPED SMOKING WITH HEART DISEASE, THERE'S ALMOST IMMEDIATE BENEFIT. AND THEN IT'S VERY DIFFICULT TO QUIT SMOKING DUE TO NICOTINE ADDICTION. BUT NOW WE HAVE DRUGS FOR THAT SUCH AS CHANTIX AND OTHER THINGS. AND SO IN THE U.S. WE'VE MADE GOOD PROGRESS AT REDUCING SMOKING. SO THERE'S LOTS OF CHEMICALS IN THE CIGARETTE SMOKE THAT CAN FORM CARCINOGENS, WE'RE GOING TO FOCUS ON POLYAEROMATIK HYDROCARBONS AND ETHYL CARBAMATE, AND NICKEL, CHROMIUM, CADMIUM IF YOUR WATER IS NOT PURE, AND HYDRAZINE IS ACTUALLY ROCKET FUEL. SO WHAT HAPPENS WITH HYDROCARBONS, THEY OXIDIZE AND CAN BIND TO DNA AND CAUSE MUTATIONS. AND WE SEE THAT CG CAN GO TO FORM TA MUTATIONS IN CERTAIN GENES, ESPECIALLY THE GENES FOR P53, AND K-RAS. SO P53 IS A TUMOR SUPPRESSOR GENE, WHEN IT GETS MUTATED IT BECOMES INACTIVE AND K-RAS WHEN IT GETS ACTIVATED IT'S AN ONCOGENE, AND THEN IT STIMULATES CANCER GROWTH. SO BENZ A PYRENE IS A HYDROCARBON WITH A SERIES OF FIVE, SIX MEMBERED RINGS, WE SEE THERE'S HYDROXYL, AND THESE CAN GET OXIDIZED ULTIMATELY LEADING TO CARCINOGENS. AND SO WE HAVE BENZ A PYRENE, THE P450 ENZYME STARTS TO OXIDIZE IT FIRST TO 7, 8 OXIDE, THEN 7, 8 DIOL AND THE ULTIMATE CARCINOGEN, BPDE, WHICH THEN BINDS TO DNA, ESPECIALLY THE GUANINES, AND FORMS ADDUCTS WITH THE DNA. ULTIMATELY LEADING TO MUTATIONS. SO THE P450 ENZYMES CATALYZE THE ADDITION OF OXYGEN, SO IT CAN FORM CARCINOGENS BUT ULTIMATELY THE CARCINOGENS WHEN THEY GET FURTHER OXYGENATED THEY ARE IN A HIGHLY SOLUBLE INACTIVE FORM AND CAN BE EXCRETED. YOU BREATHE IN THE CIGARETTE SMOKE, IT FORMS A CARCINOGEN, AND THEN ULTIMATELY YOU CAN EXCRETE THE CARCINOGEN. AND DNA ADDUCT AND INTERSTRAND DNA CROSS-LINKS CAN BE REMOVED BY ENZYMES, REPAIR ENZYMES. BUT THE BASIC PROBLEM IS IF THE RATE OF CARCINOGEN ACTIVATION EXCEEDS THE RATE OF CARCINOGEN EXCRETION, THEN YOU GET DNA MUTATION. AND SO P53, A TUMOR SUPPRESSOR GENES, GETS MUTATED. AND P53, IT'S INCREASED AFTER INITIAL DNA DAMAGE ALONG WITH P21 INHIBITOR OF CELL CYCLE ENZYMES, AND THEN WHEN P53 GETS PHOSPHORYLATED, IT INDUCES THE EXPRESSION OF BAX WHICH CAUSES APOPTOSIS OF THE CANCER CELLS, GADD45 IN DNA REPAIR AND THROMBOSPONDIN ANGIOGENESIS. IT REPAIRS THE DNA DAMAGE AND STOPPING ANGIOGENESIS BUT WHEN IT GETS MUTATED IT CAN'T DO THESE THINGS TO STOP THE CANCER CELL FROM GROWING. SO THEN THE CANCER CELL GROWS, AND IN PARTICULAR WE SEE MUTATIONS G TO T TRANSVERSIONS OCCURRING AT SPECIFIC AREAS IN THE P53 GENE, EXON 5, EXON 7 AND EXON 8. AND SO HERE WE SEE IN TERMS OF MUTATIONS, WE SEE IT'S AT CODONS 157, 158, 245, 48, 49 AND CODON 273, SO THE MUTATIONS THEN OCCUR AT SPECIFIC AREAS. IT'S NOT JUST RANDOM. SO P53 TRIES TO STOP THE CELL CYCLE GOING FROM G1, RESTING PHASE, TO THE S-PHASE, WHERE DNA IS REPLICATED. SO FOR THE CANCER CELLS TO GROW, THEY HAVE TO REPLICATE THE MUTATED DNA, AND THEN IN THE G2 PHASE THERE'S FURTHER PROTEIN SYNTHESIZE, WHICH SUPPORTS THEN THE M PHASE WHERE THE CHROMOSOMES GET SEGREGATED, AND DAUGHTER CELLS FORM FROM THE PARENT CELLS. SO INITIALLY WE HAVE ONE CELL, AND THEN WE HAVE TWO CELLS, AFTER WE GO THROUGH ONE CELL CYCLE. WHAT HAPPENS WITH CANCER CELLS IS ALMOST NONE OF THE CELLS ARE IN THE G-0 PHASE WHERE THEY REST. THEY GROW AS FAST AS THEY CAN. SO WHEN DNA GETS DAMAGED THEN, P21 GETS INCREASED, AND P53 TRIES TO DRIVE PROGRAM CELL DEATH OR APOPTOSIS. IF P53 GETS MUTATED IT'S NOT ABLE TO DO THAT. THEN WE HAVE TO LOOK AT THE CELL CYCLE ENZYMES. IN THE G1 PHASE CyclinD1 IS ACTIVE AND FORMS A DEPENDENTEN WITH 4 AND 6 AND LEADS TO THE S-PHASE, THE S-PHASE A DIFFERENT CYCLIN IS IMPORTANT, CYCLIN A, BUT WE STILL HAVE -- NOW WE HAVE CYCLIN DEPENDENT KINASE 2 THAT'S THE PARTNER FOR THE CYCLIN A. AND THEN G2 PHASE WE HAVE CYCLIN A BUT THE PARTNER CHANGED TO KINASE 1, IN M PHASE KINASE PARTNERING WITH B, CYCLINS CHANGE AND SO DO KINASES, INHINTED BY A21, 27, 57, 15, 16, 18 AND 19. BASICALLY WITH LUNG CANCER THEN WE HAVE TOBACCO SMOKE, AND IT'S A VERY LONG PROCESS. AFTER TEN YEARS OF SMOKING, THE NORMAL LUNG WILL START TO FORM WHAT'S CALLED -- UNDERGO HYPERPLASIA AND MET A PLASIA. AFTER 15 YEARS DYSPLASIA WILL FORM. AFTER 20 YEARS, A SMALL CARCINOMA IN SITU WILL FORM, AFTER 25 YEARS, THE MALIGNANT CANCER WILL FORM, AND IT CAN SPREAD THROUGH THE BODY. AND SO FOR LUNG CANCER IT STARTS IN THE LUNG, AND THEN IT CAN SPREAD TO THE LIVER, BONE, LYMPH NODES, AND THEN ULTIMATELY THE BRAIN. WHEN IT GETS INTO THE BRAIN THE PATIENT JUST HAS A FEW WEEKS LEFT TO LIVE. SO HERE WE SEE THE NORMAL LUNG CELLS IN CARTOON. THERE'S A LAYER OF SEVERAL EPITHELIAL CELLS, WITH HYPERPLASIA THE NUMBER OF CELLS INCREASES. WITH DYSPLASIA THE CELLS START TO GET DISORGANIZED, WITH A CARCINOMA IT STARTS TO FORM NOW WE'RE STARTING TO GET SOME CANCER CELLS FORMING, AND THEN ULTIMATELY THE DARK GREEN MALIGNANT CELLS FORM, AND THESE CAN UNDERGO WHAT'S CALLED EPITHELIAL MESENCHYMAL TRANSITION AND GO FROM THE LUNGS TO OTHER ORGANS. SO HERE'S A -- WHAT'S CALLED AN H AND E STAIN OF THE NORMAL LUNG. WE SEE ON THE CELL SURFACE THERE'S A FEW EPITHELIAL CELLS, THE NUCLEUS IS SHOWN IN BLUE. CYTOSOL IN PINK. THERE'S VILLI ON THE SURFACE THAT EXCHANGE GASES. YOU BREATHE IN 02, EXHALE CO2. AND THEN WE SEE WITH HYPERPLASIA, THE NUMBER OF CELLS IS INCREASED DRAMATICALLY, BUT WE STILL HAVE THE VILLI TO EXCHANGE THE GASES). NOW THE EPITHELIAL CELLS ARE BECOMING DISORGANIZED. THERE'S VILLI SO YOU CAN EXCHANGE GASES. THEN WE GET AN ADENOMA, THIS IS A BENIGN TUMOR BUT NOT AS MANY VILLI. WHEN YOU GET LUNG CANCER ULTIMATELY YOU'RE GOING TO HAVE TROUBLE BREATHING. AND THEN YOU GET AN ADENOCARCINOMA, A MALIGNANT GROUP OF CELLS, AND THESE ACTUALLY WILL START EXCRETING FLUIDS SUCH AS MUCUS AND ULTIMATELY THEY CAN BECOME MALIGNANT AND GO TO OTHER ORGANS. HERE'S A CARTOON SHOWING THE NORMAL LUNG IN WHITE. AND THEN WE GET A FEW CANCER CELLS INITIALLY, AND THEN THERE'S TUMOR PROMOTORS, SUCH AS GROWTH FACTORS IN A WILL STIMULATE THE GROWTH OF THE INITIATED CELLS, AND THEN PROGRESSION OCCURS, THERE'S MORE AND MORE MUTATIONS AND THEN A MALIGNANT CANCER FORMS THAT CAN UNDERGO METASTASIS. IT'S THOUGHT THE ORDER OF 50 GENES ARE MUTATED DURING THIS 30-YEAR PERIOD IN LUNG CANCER. AND P53 IS ONE OF THE KEY ONES THAT GETS MUTATED, IT'S A TUMOR SUPPRESSOR GENE AND THE CANCER CELLS ARE ABLE TO GROW MORE RAPIDLY, THE P53 CAN'T STOP THEM. SO INITIALLY WE HAVE A CARCINOMA SUCH AS THE LUNG, AND WHEN IT'S TUMOR GETS BIG ON THE ORDER OF 5 TO 10 MILIMETERS, IT HAS TROUBLE GETTING OXYGEN IN THE CENTER OF THE TUMOR. SO WHAT HAPPENS IS THE HOST BLOOD VESSELS WILL THEN GROW IN AND PROVIDE OXYGEN AND NUTRIENTS TO THE TUMOR, AND THEN THE TUMOR WILL FURTHER GROW AND ULTIMATELY UNDERGO METASTASIS. GENETIC ABNORMALITIES IN LUNG CANCER, WE MENTIONED P53 GETS MUTATE AND TURNED OFF, SEVERAL GENES GET SILENCED BY EPIGENETIC PHENOMENA, AND OTHER ONCOGENES GET AMPLIFIED SUCH AS CYCLIN D1, STIMULATING G1 TO S TRANSITIONS, C-MYC IS A NUCLEAR ONCOGENE, AND WE'RE GOING TO TAKE A GOOD LOOK AT THE EGF RECEPTOR, WHICH IS AMPLIFIED AND MUTATED IN LUNG CANCER, AND THE THE ERB IS ONE OF ITS PARTNERS, AMPLIFIED AND MUTATED BUT NOT AS MUCH AS EGF RECEPTOR. THIS IS A CARTOON SHOWING WHAT THE TYROSINE KINASE RECEPTORS LOOK LIKE. WE'VE GOT THE EGF RECEPTOR, WHICH HAS DOMAIN 1 AND 3, THEY BIND EGF. DOMAINS 2 AND 4 ARE MORE STRUCTURAL IN NATURE. AND THEN WE IT CROSSES PLASMA MEMBRANE ONCE, BINDS TO LIGAND ON THE OUTSIDE OF THE CELL, THE EXTRACELLULAR SPACE, AND THEN IT TURNS ON THE ENZYME ON THE INSIDE OF THE CELL THAT TYROSINE KINASE DOMAIN AND CAN PHOSPHORYLATE. THERE'S OTHER FAMILIE OF RECEPTOR TYROSINE KINASES SUCH AS IGF1 RECEPTOR, NGF RECEPTOR, PDGF RECEPTOR, FGF RECEPTOR, THE VEGF RECEPTOR THAT PLAYS A ROLE IN ANGIO GENERAL ANGIOGENESIS AND EPH RECEPTOR. WE HAVE THE EGF RECEPTOR, LOTS OF LIGANDS FOR IT. WE ESPECIALLY LOOK AT EGF AND TGF ALPHA, GROWTH FACTOR ALPHA, AND THEN THERE'S THE ERBB 2 RECEPTOR WITH TYROSINE KINASE ACTIVITY IT'S GOT NO LIGANDS. HOW DO WE TURN IT ON? WELL RECEPTORS DIMERIZE AND EGF RECEPTOR CAN FORM A HOMODIMER WHERE THERE'S TWO EGF RECEPTORS OR IT CAN FORM A HETERODIMER WHERE THERE'S ONE EGF RECEPTOR OTHER MEMBERS OF THE FAMILY INCLUDE ERRB 3 AND ERB B. EGFR IS LARGE, THIS IS WHERE EGF BINDS, 24 AMINO ACID TRANSMEMORIAL BRANS AND 541 UP KINASE ACTIVITY. LYS 721 BINDS ATP, HOLDS ON TO PHOSPATE AND TRANSFER ON THE PROTEIN SUBSTRATES. AND SO ONE OF THE WAYS IN WHICH THE EGF RECEPTOR TURNS ITSELF OFF AFTER IT'S ACTIVATED SUBSTRATE IS TYROSINE PHOSPHORYLATES ITSELF. AND SO REAL GOOD LIGANDS ARE EGF, AS WELL AS TRANSFORMING GROWTH FACTOR ALPHA, AND ONE OF THE LABS HERE AT NCI THEY ACTUALLY MAKE TGF ALPHA, PSEUDOMONAS CONJUGATES, ABLE TO BIND WITH HIGH AFFINITY TO EGF RECEPTOR BUT WHEN P38 GETS INTERNALIZED, P38 WILL KILL THE CANCER CELLS. SO THIS IS ONE THERAPY THAT NCI IS PURSUING. AND THIS IS JUST AN EXPERIMENT DONE IN THE LAB, AND WE SEE THAT HERE'S THE EGF RECEPTOR GETTING TYROSINE PHOSPHORYLATED BUT OTHER THINGS ARE RIGHT THERE. AND SO THE EGF RECEPTOR THEY WERE CAN GET MUTATED, AND ESPECIALLY WHEN WE HAVE THIS L858R MUTATION WHICH IS QUITE COMMON THEN IT'S SENSITIVE TO TYROSINE KINASE INHIBITORS, GAFITINIB AND ERLOTINIB. WE SEE THE MUTATIONS IN THE KINASE DOMAIN. HERE'S THE L858R, AND ONCE THE EGF RECEPTOR TYROSINE KINASE GETS TURNED ON, IT CAN ESPECIALLY GO THROUGH THE MAP KINASE MATHWAY TO STIMULATE GROWTH AND AKT TO STIMULATE CELL SURVIVAL. WE HAVE A SEVERAL PLAYERS HERE, EGF RECEPTOR, AND IT INTERACTS WITH THESE ADAPTOR PROTEINS, GR B 3 AND SOS, PHOSPHORYLATED, RAS GETS PHOSPHORYLATED, MEK GETS PHOSPHORYLATED, IT'S AN ENZYME THAT CAUSES PHOSPHORYLATION THEN OF THE ERK 1, 2, AND ERK 1, 2 GOES INTO THE NUCLEUS AND STIMULATES GROWTH. K-RAS GETS MUTATED IN 20 TO 30% OF LUNG CANCER PATIENTS AND WE HAVE NO THERAPY FOR IT AT THIS POINT. SO THE RAS AS WE MENTIONED GOES THROUGH GTP, AND GETS MUTATED ESPECIALLY AT CODON 12 AND UP IN FREDERICK WE HAVE A GROUP THAT'S TRYING TO WORK WITH RAS AS A MODULATOR TARGET AND COME UP WITH NEW THERAPIES. RAS IS DOWN EXTREME. IN MELANOMA, THEY CAME UP WITH THIS THAT'S RESPONSIVE IN MELANOMA. THE PROBLEM IS THEY WORK ABOUT A YEAR OR TWO, AND THEN THE CANCER MUTATES INTO SOMETHING ELSE AND THEY BECOME RESISTANT TO THESE DRUGS. CANCER, IT'S A MOVING TARGET. THAT'S THE PROBLEM. AND RAS CAN THEN PHOSPHORYLATE MEK, AND MEK 1 AND MEK 2, WE HAVE INHIBITORS, AND SO THEY ARE TRYING THIS TYROSINE KINASE TRIMETANIB AS INHIBITOR IN VARIOUS PATIENTS. AND ANOTHER ONE IS TELUMATINIB, A TYROSINE KINASE INHIBITORS. WE MENTIONED PHOSPHORYLATED ERK GOES INTO THE NUCLEUS, REGULATES ONCOGENES SUCH AS FOS, JUN AND MYC. THIS IS AN IMPORTANT PATHWAY FOR GROWTH, AND HERE IS A LITTLE CARTOON SHOWING THE EGF RECEPTOR FORMING A DIMER, AND THEN AFFECTS RAS, RAF, MEK, ERK AND ERK GOES INTO THE NUCLEUS. AND WHEN WE DO EXPERIMENTS IN THE LAB IT TAKES 30 SECONDS FOR THIS PATHWAY TO OCCUR. IT'S VERY RAPID, EXTREMELY RAPID. AND THIS IS A CARTOON SHOWING EGF RECEPTOR. HERE IS A MONOMER. BUT THEN IT FORMS A DIMER. AND WHEN YOU ADD EGF IT BECOMES AN ACTIVE DIMER AND BASICALLY WE HAVE DOMAINS 2 FROM ONE RECEIVER AND ONE PARTNER INTERACTING TO FORM THE ACTIVE DIMER AND THEN IT CROSSES THE MEMBRANE AND TURNS ON THE KINASE DOMAIN TO PHOSPHORYLATE PROTEIN SUBSTRATES. AND THEN THE OTHER BIG THING FOR THE EGF RECEPTOR IS THE SURVIVAL PATHWAY, AND TI 3 KINASE GETS STIMULATED BY ERK, WE SAW IT WAS PHOSPHORYLATED, AND CAN INTERACT WITH AKT AND mTOR TO INCREASE CELLULAR SURVIVAL. AND WHAT IT DOES IS IT INCREASES THE ANTI-APOPTOTIC PROTEIN Bcl 3. PI3 KINASE HAS A CATALYTIC SUBUNIT THAT METABOLIZES PIP2 TO PIP3, MUTATED IN SOME OF THE BREAST CANCERS. GLIOBLASTOMA, COLON AND STOMACH CANCER, BUT NOT SO MUCH LUNG CANCER. SO WHEN IT GETS MUTATED, THEN THERE'S MORE PIP3 TO STIMULATE CELLULAR SURVIVAL. AND THE PTEN INHIBITS ENZYMATIC ACTIVITY OF THE PIP3 KINASE, PHYSIOLOGICAL ANTAGONIST BUT UNFORTUNATELY PTEN GETS MUTATED IN 13% OF BREAST CANCER PATIENTS SO THEN THE PIP3 KINASE, ITS REMOVAL FROM CYTOSOL IS IMPAIRED. AND THE AKT PREVENTS APOPTOSIS OF CELLS AND IN PARTICULAR SER473 GETS PHOSPHORYLATED, AND IT THEN PHOSPHORYLATES BAD AND CASPASE 9, PREVENTING APOPTOSIS OF CANCER CELLS. AKT IS AGAIN MUTATED IN 5% OF BREAST CANCER, AND mTOR, IT'S A DOWNSTREAM FROM THE AKT, AND PEOPLE HAVE TRIED TO DEVELOP A LOT OF DRUGS FOR TREATING CANCER PATIENTS USING mTOR, AND THAT'S LARGELY BEEN UNSUCCESSFUL UNFORTUNATELY. SO THIS IS A CARTOON THEN SHOWING LUNG CANCER, WHAT THE MOLECULAR MARKERS ARE, AND WE SEE ABOUT 30% HAVE K-RAS MUTATIONS, WE HAVE NO THERAPY FOR THAT AT PRESENT. ABOUT 15 TO 20% HAVE EGF RECEPTOR MUTATIONS. WE HAVE TYROSINE KINASE ACTIVITY. HER-2 JUST A SMALL PERCENTAGE GETS MUTATIONS, BUT IT'S AN AREA THAT WE'RE INVESTIGATING BECAUSE THE HER-2 CAN FORM HETERODIMERS WITH THE EGF RECEPTOR. AND THEN THERE'S OTHER THINGS SUCH AS RET AND MET, AND YOU SEE LUNG CANCER, IT'S VERY COMPLICATED BUT WHEN WE ADD IT ALL UP WE SEE WE FIGURED OUT ABOUT 70% OF THE KEY DRIVER MUTATIONS THAT OCCUR IN LUNG CANCER, BUT WE'VE STILL GOT A WAYS TO GO. THERE'S 30% MORE THAT WE DON'T KNOW YET. THERE'S STILL A LOT OF WORK TO BE DONE IN LUNG CANCER. AND THIS IS A CLINICAL EXAMPLE OF A PROTOCOL THAT NCI HAS GOING FOR LUNG CANCER. SO YOU DO THE BIOPSY AND YOU DO A GENETIC ANALYSIS, AND IF YOU SEE EGF RECEPTOR MUTATIONS YOU TREAT THE PATIENT WITH ERLOTINIB, EGF RECEPTOR KINASE INHIBITOR. IF YOU DON'TS SEE EGF RECEPTOR MUTATIONS, YOU LOOK FOR RAS, RAF OR MEK MUTATIONS. IF YOU SEE THAT YOU TREAT THEM WITH A MEK INHIBITOR, EZD6244. IF YOU DON'T SEE THAT LOOK FOR PTEN, AKT MUTATIONS, IF YOU SEE THAT TREAT WITH PIP3 KINASE INHIBITOR MK 2006. LOOK FOR ERB MUTATION, TREAT THE PATIENT WITH ERLOTINIB. IF YOU DON'T SEE THAT LOOK FOR KIT MUTATION, PDGF RECEPTOR A MUTATIONS, TREAT THEM WITH ZANITONINIB, IF YOU DON'T SEE THAT, WELL, YOU RUN OUT OF OPTIONS SOONER OR LATER. BUT THEN IN THE END WHEN YOU'RE ALL DONE WITH THE TREATMENT, YOU AGAIN DIAGNOSE THE TUMOR BECAUSE WE MENTIONED THAT THERE'S THIS -- THE TUMOR CAN UNDERGO FURTHER MUTATIONS AND BECOME UNRESPONSIVE TO THE DRUG IT INITIALLY RESPONDED TO. SO YOU SEE HOW THE MOLECULAR ANALYSIS THEN DICTATES THE THERAPY OF THE PATIENT. AND THIS IS JUST A CARTOON SORT OF ILLUSTRATING NOT ONLY DOES THE EGF RECEPTOR GET ACTIVATED, BUT DOWNSTREAM -- UPSTREAM TARGETS CAN ULTIMATELY ALSO ACTIVATE THE EGF RECEPTOR. SO THIS IS WHY IT'S SO IMPORTANT IN LUNG CANCER. SO WE MENTIONED THAT THERE'S RESISTANCE AND OFTENTIMES IT'S DUE TO SECONDARY MUTATION TO T790M, THE PATIENT IS NO LONGER RESPONSIVE TO ERLOTINIB OR GIFITNIB. ANOTHER DISEASE THAT OCCURS IN CML PATIENTS, LEUKEMIA PATIENTS, IS WHAT HAPPENS WHEN THERE'S A TRANSLOCATION FROM CHROMOSOME 22 AND CHROMOSOME 9, AND THEN WHAT HAPPENS IS THIS FUSED BCR-ABL GENE FORMS AND THIS STIMULATES TYROSINE KINASE ACTIVITY, SO THEY HAVE COME UP WITH A TYROSINE KINASE INHIBITOR THAT WORKS AGAINST THAT, AND THAT'S GLEEVEC. SO WE SEE WE HAVE CHROMOSOME 22 AND CHROMOSOME 9, AND THERE'S A BREAK POINT, TRANSLOCATION, AND THEN WE HAVE A FUSE bcr-abl GENE, AND THEN THIS IS EXPRESSED IN THE CANCER CELL, STIMULATING GROWTH. AND SO HERE WE SEE WE HAVE CHROMOSOME 9, AND CHROMOSOME 22, AND THERE'S A TRANSLOCATION, AND THE BCR-ABL GENE IS ON CHROMOSOME 22 THEN, AND THE GENE APPARENTLY BECOMES SMALLER, WHEREAS CHROMOSOME 9 APPEARS TO BECOME LARGER. YOU SEE CHROMOSOME 9 AFTER THE TRANSLOCATION, IT'S LARGER, CHROMOSOME 22 AFTER THE TRANSLOCATION IS ACTUALLY SMALLER. AND SO WITH THESE DRUGS, YOU ALWAYS WANT TO IMPROVE THE THERAPEUTIC RESPONSE AND MINIMIZE TOXICITY, AND WITH THESE TYROSINE KINASE INHIBITORS OFTENTIMES THERE'S A SKIN RASH, AND SOMETIMES THERE'S NAUSEA. YOU TRY TO USE THE LOWEST DOSE POSSIBLE TO CAUSE A THERAPEUTIC RESPONSE AND MINIMAL TOXICITY. AFTER A YEAR THEY HAD 54 PATIENTS, 53 OUT OF 54 RESPONDED. AND AFTER FIVE YEARS, 89% WERE STILL RESPONSIVE. AND WE SEE WHEN YOU HAVE THE GLEEVEC, IT BLOCKS ATP FROM GETTING IN AND DONATING THE PHOSPATE THEN TO A TYROSINE ON A SUBSTRATE. AND GLEEVEC GETS A SMALL MOLECULE. SO AFTER FIVE YEARS, SOME OF THE PATIENTS BECAME RESISTANT AND THERE WERE ADDITIONAL MUTATIONS IN THE BCR-ABL GENE. SO WHAT THE RESEARCHERS THEN DO IS THEY TRY TO DEVELOP A SECOND GENERATION OF TYROSINE KINASE INHIBITORS. SO THIS IS THE WAY CANCER IS. THE HUMAN COMES UP WITH A THERAPY. THE CANCER COMES UP WITH SOMETHING ELSE. THEN THE HUMAN HAS TO GO BACK AND TRY TO COME UP WITH NEW DRUGS. SO FOR CML, THE TYROSINE KINASE INHIBITORS ARE IMITANIB, DASATANIB. BREAST CANCER WE HAVE HERCEPTIN AND LAPATANIB. MELANOMA, PLX4032. GASTROINTESTINAL STROMAL TUMORS TARGET IS RECEPTOR KINASE C-KIT. WE HAVE IMATINIB, AND SUNITINIB. FOR EGF RECEPTOR PHASE 2 GEFITINIB AND ERLOTINIB, AND THERE'S NOW PHASE 2 DRUGS FOR THAT. SO HOW CAN WE PREVENT CANCER? I HAVE A LITTLE LIST HERE. AND THE FIRST THING YOU WANT TO DO IS CHECK YOUR HOUSE FOR RADON. I USED TO LIVE IN FREDERICK COUNTY ON A HILL, AND THEN I WENT TO SELL THE HOUSE AND MOVE INTO MONTGOMERY COUNTY. AND WHEN I WENT TO SELL THE HOUSE THEY SAID YOU'VE GOT TOO MUCH RADON IN YOUR BASEMENT. IF YOU LIVED IN THAT BASEMENT IT WOULD HAVE BEEN THE EQUIVALENT OF SMOKING THREE PACKS OF CIGARETTES A DAY. WELL, WE LIVED UPSTAIRS, BUT TO SELL THE HOUSE THEY SAID YOU'VE GOT TO PUT IN A PUMP TO BLOW OUT THE BAD AIR IN THE BASEMENT AND GOOD AIR WILL COME IN AND THE RADON WILL GO DOWN. AND SO MOST OF THE HOUSES HERE IN MARYLAND HAVE RADON PUMPS NOW, IF YOU HAVE A BASEMENT. SECOND THING, CHECK YOUR HOUSE FOR ASBESTOS. WE MENTIONED OLD HOUSES IN THE WALLS, THE INSULATION HAS A LOT OF ASBESTOS IN IT. TAKE PRECAUTIONS AT YOUR WORKPLACE. MANY OF THE BUILDINGS HERE AT NIH ARE VERY OLD, SUCH AS I USED TO HAVE AN OFFICE IN BUILDING 31, AND THERE WAS A LITTLE SIGN, WARNING, THESE WALLS CONTAIN ASBESTOS. MODERN BUILDINGS HERE, THEY ARE ASBESTOS FREE BUT STILL THE OLD BUILDINGS AT NIH HAVE ASBESTOS IN THEM. CHECK YOUR COMMUNITY WATER SYSTEM. WE MENTIONED THAT IF THERE'S CERTAIN METALS SUCH AS CHROMIUM, THIS CAN LEAD TO LUNG CANCER. AND SO YOU WANT TO HAVE GOOD AIR IN YOUR HOUSE. YOU WANT TO AVOID BREATHING POLLUTED AIR SUCH AS I USED TO LIVE IN LOS ANGELES, WHERE THERE'S TREMENDOUS AMOUNTS OF OZONE IN THE AIR. AND I WAS TOLD, I WENT TO GRADUATE SCHOOL FOR FIVE YEARS, THEY SAID EVERY YEAR YOU LIVED HERE YOU'RE USING HALF A YEAR OF YOUR NATURAL LIFESPAN. BECAUSE THE AIR IS SO BAD. AND I WENT TO SCHOOL AT CAL TECH, AND EVERY DAY AROUND 1:00 MY LUNGS WOULD START BURNING, BECAUSE THE AIR, THE OZONE FROM DOWNTOWN THEN PASSED THROUGH PASADENA, BUT BY 5:00 IT WAS GONE, IT HAD GONE DOWN TO RIVERSIDE. THEY WERE BREATHING THE BAD AIR. OKAY. AND PROTECT YOUR SKIN. WE MENTIONED IF YOU GO OUT IN THE SUN USE LOTS OF SUNSCREEN. DON'T BREATHE SMOKE SUCH AS IF YOU'RE AROUND A SMOKER, THE SECONDARY SMOKE ISN'T GOOD FOR YOU. EXERCISE DAILY. MY BIG THING IS RIDING BICYCLES, AND THIS WEEKEND WE HAVE THE CIVIL WAR CENTURY, YOU RIDE FOR 100 MILES THROUGH THE BATTLEFIELDS OF GETTYSBURG AND ANTIETAM. AVOID PESTICIDES. CERTAIN PESTICIDES ARE IMPLICATED IN PROSTATE CANCER. EAT LOTS OF FRUITS AND VEGETABLES. THESE CONTAIN REDUCTANTS THAT PREVENT GENERATION OF CARCINOGENS. REDUCE RED MEAT CONSUMPTION, ESPECIALLY IT HAS LOTS OF FAT. EAT FISH ENRICHED IN OMEGA 3 FATTY ACIDS, MINIMIZE FRIED FOODS, IF YOU GO TO THE RESTAURANT YOU HAVE A CHOICE, YOU WANT YOUR SEAFOOD BROILED OR FRIED. I CHOOSE BROILED. DRINK ALCOHOL IN MODERATION. YOU DON'T WANT TO GET LIVER CANCER. AVOID UNNECESSARY X-RAYS. AND REDUCE INFECTIONS. IT'S FOUND ABOUT 20% OF THE CANCERS COME FROM CONSTANT INFLAMMATION. SO INFECTIONS SORT OF START THE INFLAMMATION, AND THEN IT CONTINUES. WE HAVE A COUPLE REFERENCES HERE. ABOUT HALLMARKS OF CANCER, AND ESPECIALLY THE bcr-abl PATHWAY. AND THAT'S ABOUT IT FOR ME SO I'D BE HAPPY TO ANSWER ANY QUESTIONS IF YOU HAVE THEM. IF NOT, WE'LL MOVE ON TO PETE. OKAY, SO PETE CHOYKE, HE IS AN M.D. FROM JEFFERSON MEDICAL COLLEGE. HE DID HIS DIAGNOSTIC RADIOLOGY RESIDENCY AT YALE NEW HAVEN HOSPITAL, IMAGING FELLOWSHIP AT UNIVERSITY OF PENNSYLVANIA, HE JOINED FACULTY AT GEORGETOWN, IN 2004 WE WERE SMART ENOUGH TO RECRUIT HIM HERE TO NCI, IMAGING SECTION, TITLE IS "IMAGE OF OF CANCER." PETE? OOPS, GOT TO GIVE YOU THE MICROPHONE. >> WELL, TERRY, WE'RE ON THE EXACT SAME CYCLE WE WERE ON LAST YEAR BECAUSE YOU WERE GOING TO DO THAT CIVIL WAR THING LAST YEAR. >> IT'S THE WEEK AFTER LABOR DAY EVERY YEAR. >> YEAH, SO THIS WAS LIKE A REGULAR THING. I'M GOING TO BE SITTING AROUND, BUT YOU ENJOY YOURSELF. SO I'M A BIKER BUT I'M NOT A CENTURY. GOSH, THAT'S CRAZY. SO PETE CHOYKE, I'M A RADIOLOGY IN THE NCI, AND SINCE THIS IS AN INTRODUCTORY COURSE, OR CLASS BASICALLY, I THOUGHT WHAT I WOULD DO IS TAKE YOU AROUND VIRTUALLY A RADIOLOGY DEPARTMENT, AND SORT OF GO INTO WHAT MAKES EACH OF THESE SCANNERS WHAT THEY ARE. AND SORT OF YOU HAVE TO UNDERSTAND MANY RADIOLOGISTS ARE KIND OF CLOSET GEEKS, AND WE LOVE THE EQUIPMENT, AND THE PHYSICS AND THINGS LIKE THAT. SO I WON'T -- NO EQUATIONS BUT WE'LL TALK ABOUT HOW THESE WORK. IMAGING IS AN IMPORTANT ASPECTS OF CANCER. THERE'S SCREENING TECHNIQUES THAT ACTUALLY LOOK FOR CANCER. THERE ARE STAGING TECHNIQUES WHERE THE CANCER IS EITHER KNOWN OR SUSPECTED, YOU WANT TO SEE THE EXTENT OF IT. AND THEN ONCE THE PATIENT STARTS TREATMENT WE WANT TO SEE WHETHER THE LESION IS DECREASING, SO WE MONITOR THE PATIENT AND AFTER THE LESION DISAPPEARS HOPEFULLY WE CHECK FOR RECURRENCE SO THERE'S SORT OF A SCREENING ON THE POST-TREATMENT SIDE, HAS IT COME BACK, ULTIMATELY ALTOGETHER THE IMAGING PORTFOLIO OF A PATIENT DETERMINES HIS OR HER PROGNOSIS, WHAT WILL HAPPEN TO THE PATIENT. SO IN THE MODERN IMAGING DEPARTMENT, THERE ARE A NUMBER OF TYPES OF SCANS THAT YOU'LL ENCOUNTER, THE CT, MRI, ULTRASOUND, SPECT AND PET. OPTICAL IMAGING IS ONE THAT MIGHT BE THERE IN THE FUTURE, BUT FOR NOW THAT'S NOT WHAT WE'RE GOING TO TALK ABOUT. SO THE QUIZ IS NAME THAT SCANNER. I DON'T EVEN KNOW THE ANSWER TO ALL OF THIS, BECAUSE MANY OF THESE SCANNERS LOOK EXACTLY THE SAME. THEY HAVE A BED FOR THE PATIENT. THERE'S A DOUGHNUT HOLE WHERE THE SCANNING APPARATUS IS, AND THEN INSIDE THE RING IS SOME KIND OF IMAGING. SO THIS, FOR INSTANCE, COULD BE A CT OR AN MRI. WE KNOW THIS IS GOING TO BE A SPECT WITH TWO FLAT PLATES WHERE SPECT IMAGING TAKES PLACE. AND WE'LL EXPLAIN ALL THAT. AND THIS IS A PET SCANNER. THE OUTLIER OF COURSE IS THE ULTRASOUND, IT LOOKS VERY, VERY DIFFERENT AND WE'LL TALK ABOUT WHY THAT IS. SO LET'S TALK ABOUT CT, WHICH IS THE WORK HORSE OF THE DEPARTMENT. VIRTUALLY EVERY PATIENT AT NIH ENDS UP GOING THROUGH THE CT DEPARTMENT. AND THIS IS A PATIENT WITH A LUNG CANCER, AND YOU CAN SEE THE LUNGS HERE, AND HERE. AND THERE'S A MASS IN THE LEFT LUNG. THAT'S THE WAY WE NAME THESE. LEFT IS ON THE RIGHT SIDE OF THE SCREEN, THE RIGHT IS ON THE LEFT PART OF THE SCREEN, AS IF YOU WERE LOOKING FROM THE PATIENT'S FOOT TOWARD THEIR HEAD. THAT'S THE ORIENTATION FOR ALL THESE SCANNERS. AND YOU CAN SEE THIS DENSE LESION WITH SPECULATIONS COMING OFF OF IT. THAT'S THE HALLMARK OF TUMOR. YOU HAVE TO UNDERSTAND ONE THING ABOUT THESE IMAGES THEY ARE INHERENTLY DIGITAL IMAGES, NOT PHOTOGRAPHS. AND YOU CAN CHANGE THE WAY THE IMAGE LOOKS BY TWIDDLING DIALS, SPECIFICALLY THE WINDOW LEVEL. THE WINDOW GIVES YOU THE GRAY SCALE, IN OTHER WORDS HOW MANY UNITS OF GRAYSCALE THEY WILL BE SPREAD OVER, SO IN THIS CASE 400, OR TO SEE THE LUNGS YOU MAKE THAT WINDOW MUCH WIDER, 1500. SO THE WHOLE SCALE IS 2,000, FROM MINUS 1,000 TO POSITIVE 1,000. SO IT'S A 2000 SCALE. YOU CAN SET THAT WINDOW AND SEE HOW THIS WILL BE A CONTRASTING WINDOW BECAUSE THE GRAYSCALES WILL BE MUCH MORE CLOSE TO EACH OTHER. THERE'S THE SECOND NUMBER, THE LEVEL, WHICH MERELY SETS WHERE THE MIDDLE OF THE GRAYSCALE IS GOING TO BE. SO BY CHANGING THE LEVEL IN THE WINDOW YOU CAN GET DRAMATICALLY DIFFERENT IMMUNE -- IMAGES. I WILL START WITH THE MEDIASTINAL WINDOW. AND THERE'S A NODULE HERE YOU CAN SEE. THERE'S THEN WE WILL -- I'LL SWITCH TO THE LUNG WINDOW. THESE ARE PRE-SET IN THE MACHINE. AND YOU CAN CHECK OUT ALL OF ASPECTS OF THE LUNG. THERE'S A BONE WINDOW THAT OPTIMIZES FOR BONE, AND THEN THERE ARE VARIOUS SOFT TISSUE WINDOWS THAT YOU CAN SET UP. SO THIS IS THE GRAYSCALE THAT I'M TALKING ABOUT FROM BLACK TO VERY WHITE. THAT'S THE GRAYSCALE. THE QUESTION IS WHETHER YOU MAKE THAT OVER THE FULL 1,000 RANGE OR 1500 RANGE OR NARROW IT FOR THE MEDIASTINAL WINDOW. SO CT IS A WONDERFUL TECHNIQUE. IT'S WIDELY AVAILABLE. IT'S GOT MINIMAL PREPARATION FOR THE PATIENT. THE ONLY THING WE ASK IS THAT THEY DRINK A RADIODENSE CONTRAST MATERIAL WHICH HAS EITHER HAD A LITTLE IODINE IN IT OR BARIUM. AND THEN THE PATIENT'S BROUGHT ON TO THE SCANNER, THEY MAY HAVE HAD AN I.V. PLACED IN THEIR ANTI-CUBITAL PART, AND THEN THEY MAY GET CONTRAST, THEY MAY NOT GET CONTRAST BUT IN EITHER CASE THE TOTAL AMOUNT OF SCAN ON MODERN SCANNER IS 2 TO 3 SECONDS, IT'S DONE. THEY ARE EXTREMELY FAST, VERY HIGH RESOLUTION, IN THE COMPARISON RELATIVELY INEXPENSIVE PARTLY BECAUSE THE THROUGHPUT IS SO GREAT YOU DON'T HAVE TO CHARGE A LOT PER PATIENT TO MAKE BACK THE COST OF THE SCANNER SO THEY ARE RELATIVELY INEXPENSIVE. AROUND THE WORLD CT IS BECOMING MORE COMMON. IT USED TO BE RESERVED FOR DEVELOPED WORLD BUT NOW THE DEVELOPING WORLD COMMONLY HAS ACCESS TO CT. NOT ALL PARTS OF THE DEVELOPING WORLD. AFRICA IS A SAD EXCEPTION BUT OTHER PARTS OF THE WORLD. NOW, IT'S NOT WITHOUT ITS ISSUES. CT DOES REQUIRE RADIATION AND WE'LL TALK ABOUT THAT. AND IT OFTEN REQUIRES THIS INTRAVENOUS CONTRAST MEDIA WHICH CAN RESULT IN ALLERGIC REACTIONS, THEY ARE VERY FEW BUT CAN OCCUR AND CAN RESULT IN SOME KIDNEY DAMAGE IN PATIENTS WHO HAVE PREEXISTING KIDNEY DISEASE. SO WE'RE VERY CAREFUL NOT TO GIVE CONTRAST TO PATIENTS WHO HAVE ALREADY HAD KIDNEY DISEASE. AND FUNDAMENTALLY THE ONLY THING YOU GET OUT OF A CT IS ANATOMY. NOW, THAT'S REALLY IMPORTANT. I MEAN, ANATOMY IS 9/10 OF IT BUT IT'S ONLY ANATOMY AND CAN'T TELL YOU WHETHER SOMETHING'S FUNCTIONING, FOR INSTANCE IT'S ALIVE OR DIVIDING OR METASTASIZING. IT ONLY SAYS THAT THIS IS WHERE IT IS AT THIS POINT IN TIME. SO WHETHER YOU GET A CHEST X-RAY OR CT SCAN FUNDAMENTALS ARE THE SAME, IN THAT WHAT WE DO IS WE HAVE A VERY HIGH VOLTAGE CIRCUIT THAT ESSENTIALLY BOILS OFF ELECTRONS FROM A COIL, AND ACCELERATES THEM TOWARDS AN ANODE, WHICH IS DEMARCATED HERE, AND YOU CAN SEE IT'S ANGLED SO THAT WHEN IT IMPACTS THIS TUNGSTEN ANODE, IT WILL RELEASE X-RAYS, SO THESE ELECTRONS BANG INTO THE TUNGSTENS, AND RELEASE IN THE TRANSFER OF ENERGY RELEASE AN X-RAY, VERY HIGH ENERGY -- NOT VERY HIGH BUT HIGH ENOUGH TO PENETRATE THROUGH THE BODY OF A PATIENT. NOW, THAT'S THE SAME FOR A CHEST X-RAY OR CT SCANNER, BUT ON A CT SCANNER THIS X-RAY TUBE ROTATES AROUND THE PATIENT, 360 DEGREES. AND SO YOU GET THIS COMPLETE REVOLUTION AROUND THE PATIENT, AS THEY LIE ON THE TABLE. SO THIS IS CALLED THE GANTRY, AND THIS IS THE TABLE. SO IN ADDITION TO THIS X-RAY TUBE, YOU CAN SEE THIS RING OF DETECTORS. SO RATHER THAN USE FILM TO PICK UP THE X-RAY, WE USE ELECTRONIC DETECTORS THAT DETECT THE ENERGY THAT'S BEING RELEASED BY THE X-RAY, AND THAT'S CONVERTED INTO A LITTLE BIT OF LIGHT THAT'S DETECTED AND THAT'S RECORDED AS SIGNAL. NOW, BY ITSELF, IT'S RAW DATA. IT'S NOT AN IMAGE. IT HAS TO BE RECONSTRUCTED TO FORM AN IMAGE. AND SO THERE ARE MANY WAYS OF RECONSTRUCTION, BUT JUST TO GIVE YOU THE CONCEPT OF WHAT'S GOING ON, YOU HAVE -- I HAVE THIS DRAWING HERE. SO IF WE HAVE FOUR SAMPLES IN THE CENTER OF THE GANTRY, AND YOU HAVE AN X-RAY SOURCE, YOU CAN SEE WHAT WOULD HAPPEN IN THIS DIRECTION. YOU'D GET A LOT OF ATTENUATION OF THE X-RAY BECAUSE OF THE TWO SAMPLES BEING LINED UP, AND THAT WOULD BE RECORDED HERE. AND THEN YOU'D GET TWO OTHER ATTENUATIONS OF A LESSER DEGREE, BECAUSE OF THESE TWO SAMPLES HERE. WHEN YOU GO TO THIS POSITION, WITH THE X-RAY, YOU ONLY SEE TWO. AND IN THIS ONE IT LOOKS VERY SIMILAR TO THAT ONE. IN THIS ONE IT LOOKS VERY SIMILAR TO THAT ONE. BY DOING THAT OVER AND OVER AGAIN AND BACK-PROJECTING THESE, YOU START TO RESOLVE THE FOUR SAMPLES THAT YOU'RE AFTER. AND THAT'S ESSENTIALLY WHAT HAPPENS. AND WE DO THAT AT EVERY SLICE, SO YOU DO THAT AT THIS SLICE, AND MULTIPLE SLICES. AND YOU EVENTUALLY GET A STACK, 3D VOLUME OF WHAT'S IN THERE. NOW, IT'S A LOT MORE COMPLICATED FOR A HUMAN BODY THAN FOR THINGS, AND THERE'S A LOT OF MASSAGING OF THE DATA TO GET THE IMAGES WE SEE. FUNDAMENTALLY THAT'S WHAT IT IS. IT'S A RECONSTRUCTION ALGORITHM THAT DOES THAT. AND SO IF WE LOOK AT MODERN CT SCANNER WITH A PATIENT IN IT THERE'S THE X-RAY SOURCE ROTATING AROUND. BY THE WAY THIS IS ROTATING EXTREMELY FAST. NOT STEP, STEP, STEP, STEP. IT'S ROTATING LIKE A TURBINE ON A JET. IN FACT, IT'S NO ACCIDENT THAT GENERAL ELECTRIC, FOR INSTANCE, MAKES TURBINES IN A JET AND CT SCANNERS. BECAUSE IT'S THE EXACT SAME KIND OF MECHANICAL TEE VICE THAT ALLOWS IT TO MOVE CONTINUOUSLY AND VERY FAST WITHOUT FLYING OUT INTO THE ROOM. SO THEN THERE ARE ALL THESE DETECTORS AND DATA ACQUISITION SYSTEMS BOLTED TO THE GANTRY SO YOU CAN GET RECONSTRUCTION TIMES THAT ARE FAST. SO VIRTUALLY AS THE PATIENT'S GETTING OFF THE TABLE THE ENTIRE SCAN IS RECONSTRUCTED, ALL THE BACK PROJECTION I TALKED ABOUT, ALL THAT COMPUTATION IS DONE IN SECONDS, AND THE IMAGES ARE CREATED. AND SO WE -- TYPICALLY WE'RE USED TO LOOKING AT A CT SCANNER LIKE THIS WITH A SPINE HERE AND KIDNEYS, LIVER, BUT IT'S A 3D DATASET AND IT'S VERY EASY TO SIMPLY RECONSTRUCT THAT DATASET IN THIS PLANE, SO HERE ARE THE KIDNEYS, LIVER AND SPLEEN, ALL THE BONES, OR IN THE SAGITTAL PLANE, HERE YOU SEE THE SPINE, AND THAT'S ROUTINE WITH EVERY SINGLE CT, YOU GET ALL OF THAT SO YOU CAN PRESENT IT IN ANY WAY THAT'S OPTIMAL TO SEE THE PATHOLOGY THAT YOU WANT TO SEE. IN FACT, WE'RE NOT LIMITED TO THESE THREE PLANES. YOU CAN TAKE ANY ARBITRARY PLANE, OR SOMETIMES WE TAKE A CURVED PLANE, FOR INSTANCE TO FOLLOW THE SPINE THAT DOES THIS KIND OF S THING, YOU CAN DRAW AN S-SHAPED SPINE AND THEN RECONSTRUCT ALONG THAT. SO YOU CAN DO THAT. SO THAT'S THE BEAUTY OF A DIGITAL IMAGE. NOW, THE OTHER THING THAT WE'RE ALWAYS CONCERNED ABOUT IS RADIATION, TO THE PATIENT, AND WE KNOW THAT DIFFERENT PARTS OF THE BODY WILL HAVE DIFFERENT X-RAY ATTENUATION. YOU CAN ACTUALLY ADJUST THE AMOUNT OF RADIATION FOR THAT AREA. AS YOU GO, FOR INSTANCE, THE SCAN GOES THROUGH THE CHEST MAINLY FILLED WITH AIR THERE'S MUCH LESS ATTENUATION, AND SO YOU CAN DECREASE THE AMOUNT OF X-RAYS THAT YOU'RE PRODUCING AS YOU GO THROUGH THE LUNG. AS YOU START GETTING INTO THE BELLY, MUCH MORE DENSITY, YOU HAVE TO BOOST THE X-RAY ENERGY TO ACCOMMODATE. NOW, ONE OF THE IMPORTANT THINGS THAT WE'RE WORKING ON IS LOWERING THE ENERGY, LOWERING THE RADIATION DOSE TO PATIENTS. AND WE'VE ACTUALLY MADE DRAMATIC -- VERY DRAMATIC CHANGES, IMPROVEMENTS, IN THE AMOUNT OF RADIATION PER CT SCAN. AND A LOT OF IT IS JUST AWARENESS. SO ONCE PHYSICIANS WERE MADE AWARE THAT YOU COULD REDUCE THE AMOUNT OF RADIATION, THEY JUST ADJUSTED THE -- YOU KNOW, WHAT THEY SCANNED, HOW MUCH ENERGY THEY USED, AND A BUNCH OF FACTORS TO REDUCE THE AMOUNT OF ENERGY COMPARED OR RADIATION COMPARED TO THE BENCHMARK OR THE BASELINE. AND SO SOME OF THE TRICKS WE USE IS TO LOWER THE ENERGY OF THE X-RAY BEAM, THE SO-CALLED KILOVOLTAGE. WE CAN GET MORE SENSITIVE DETECTORS THAT DON'T REQUIRE AS MUCH ENERGY, BETTER RECONSTRUCTION ALGORITHMS CAN DECREASE AMOUNT OF RADIATION, AND WE CAN ACTUALLY CREATE SO-CALLED SYNTHETIC IMAGES SO IT'S NOT ALTOGETHER NECESSARY FOR INSTANCE TO DO A SCAN BEFORE AND AFTER CONTRAST, WE CAN JUST TAKE THE AFTER CONTRAST AND SUBTRACT OUT THE IODINE AND THE OTHER THINGS THAT WERE ADMINISTERED, AND YOU CAN GET A SYNTHETIC PRE-CONTRAST IMAGE WITHOUT THE DOSE INVOLVED WITH THAT. SO THAT'S A COOL THING. SO THIS IS THE IDEA BEHIND ONE OF THESE SYNTHETIC IMAGES, BEFORE AND AFTER CONTRAST. YOU CAN SEE WHAT HAPPENS WITH CONTRAST THERE'S THIS BRIGHTENING OF TISSUE, LIKE THE LIVER AND KIDNEYS ARE BRIGHTER, THE CYST IS NOT CHANGING IN DENSITY BUT THE REST OF THE KIDNEY IS BRIGHTER. WHY? BECAUSE IT CONTAINS IODINE. AND IODINE BLOCKS THE X-RAY. IT'S A VERY DENSE ATOM, AND IT ABSORBS THE X-RAY. SO WHY IS IT BRIGHTER? WE'VE ADJUSTED THE IMAGE SO THAT THINGS THAT ATTENUATE MORE ARE BRIGHTER BECAUSE THAT'S THE WAY WE THINK. IT'S COMPLETELY ARTIFICIAL. SO BECAUSE WE WANT TO SEE THINGS ENHANCED, THAT IS GET BRIGHTER WITH CONTRAST. WE MAKE IT THAT WAY. SO THAT'S THE WAY IT LOOKS. AND IT'S USUALLY ADMINISTERED BY A PUMP THAT SITS ALONGSIDE THE SCANNER, AND I HAVE SOME PICTURES OF THAT. SO THERE'S ONE OF THE SYRINGES HAS THE CONTRAST IN IT, AND THE OTHER IS A FLUSH OF SALINE OR SOME KIND OF WATER THAT JUST PUSHES THE REST OF THE CONTRAST INTO THE PATIENT, AND FLUSHES THE SYSTEM. AND SO HERE ARE THE TWO SYRINGES. AND HERE'S THE CONTRAST MEDIA THAT WE USE. SO WE USE NON-IONIC IODINATED CONTRAST MEDIUM. THIS IS ONE EXAMPLE OF A FORMULATION, VERY TYPICAL TO HAVE BENZENE RING WITH THREE IODINES ATTACHED AND A BUNCH OF OTHER MOIETIES ATTACHED TO MAKE IT ISODENSE OR ISO OSMOLAR WITH THE BLOOD. IT'S VERY IMPORTANT BECAUSE WE ACTUALLY GIVE A HUGE AMOUNT OF IODINE, 30 TO 45 GRAMS OF IODINE, FOR A CT SCAN. I MEAN, NONE OF THE DRUGS THAT ARE ADMINISTERED TO PATIENTS ARE MEASURED IN GRAMS USUALLY, BUT HERE ROUTINELY WE GIVE HUGE AMOUNTS OF IODINE. BUT THE GOOD NEWS IS WITH NORMAL KIDNEYS, THIS IS EXCRETED VERY RAPIDLY, AND IT'S ALL GONE WITHIN 24 HOURS. PATIENTS ARE ADVISED TO DRINK, TO HYDRATE SO THEY PUSH THINGS OUT WITH GOOD HYDRATION. YOU KNOW, IT'S PRETTY AMAZING, AND THIS HAPPENS EVERY DAY WITHOUT ANY ILL EFFECTS. SO LET'S GO ON TO THE NEXT MIRACLE OF MODERN SCIENCE, MRI. AND SO THIS IS COMPLETELY DIFFERENT MODALITY, EVEN THOUGH AT SOME POINT IT KIND OF LOOKS THE SAME. THIS IS A PROSTATE MRI, WHICH I HAPPEN TO DO A LOT OF. AND THERE'S A TUMOR HERE. HERE'S THE PROSTATE SPECIMEN SHOWING WHERE THE PATHOLOGIST HAS OUTLINED THIS BIG TUMOR. THERE ARE A COUPLE OTHER LITTLE TUMORS TOO BUT THE BIG TUMOR IS VERY WELL RECAPITULATED ON THE MRI. SO MRI HAS SOME AMAZING ADVANTAGES. IT DOESN'T INVOLVE ANY RADIATION. AT LEAST NO IONIZING RADIATION. YOU CAN OBTAIN IT IN ANY PLANE THAT YOU'D LIKE, AND IT HAS A VARIETY OF THE DIFFERENT WAYS TO CONTRAST THE IMAGE, SO YOU CAN USE ALL THESE DIFFERENT PARAMETERS, T1 WEIGHTING, T2 WEIGHTING, DIFFUSION WEIGHTING, CONTRAST ENHANCED, SPECTROSCOPY, AND 20 OTHER WAYS TO BRING OUT CONTRAST IN THE PATIENT. THAT'S A HUGE ADVANTAGE. THERE ARE SOME DISADVANTAGES TO IT. IT'S CONSIDERABLY SLOWER THAN CT. SO AN MRI SCAN TAKES 30 MINUTES, OR 45 MINUTES, WHEREAS A CT TAKES A FEW SECONDS REALLY. IT TENDS TO BE MORE EXPENSIVE. DOESN'T DO VERY WELL WITH CALCIFICATIONS, SO IF THAT'S IMPORTANT, THIS IS NOT THE MODALITY. AND THEN THERE ARE SOME SIGNIFICANT SAFETY ISSUES THAT HAVE TO BECOME BUILT INTO YOUR SYSTEM SO THAT YOU DON'T HAVE CATASTROPHES, BECAUSE THIS IS ACTUALLY A VERY, VERY STRONG MAGNET IN THE MRI. IT'S A HUNDRED-FOLD STRONGER OR A THOUSAND-FOLD STRONGER THAN THE EARTH'S MAGNETIC FIELD, AND SO ORDINARY OBJECTS LIKE SCISSORS OR OXYGEN TANKS BECOME PROJECTILES IN AN MRI SUITE. AND THEY CAN ACCELERATE INTO THE SCANNER. IF SOMEBODY'S IN THERE THEY CAN CAUSE A LOT OF DAMAGE. PEOPLE HAVE BEEN KILLED IN THIS WAY. SO WE HAVE -- WE WORK VERY HARD TO MAINTAIN A SAFE ENVIRONMENT, IN WHICH WE DON'T ALLOW THOSE KIND OF METALLIC PROJECTILES TO COME ANYWHERE CLOSE TO THE MRI, WE HAVE PEOPLE WHO ARE HIGHLY TRAINED TO MAKE SURE ANYBODY WHO ENTERS THE ROOM HAS BEEN PRE-SCREENED FOR ANY KIND OF POTENTIAL PROJECTILES, AND THERE'S JUST AN AWARENESS, AN ALERTNESS THAT HAS TO SURROUND AN MR SCANNER. MR SCANNER, EVEN THOUGH LIGHTS ARE OUT, IN THE MIDDLE OF THE NIGHT, THE MRI, THE MAGNET IS STILL ON. AND SO THAT'S ONE OF THE GOSPELS THAT WE TALK ABOUT, THE MAGNET IS ALWAYS ON. 24/7. SO, YOU KNOW, EVEN WHEN THE GUYS COME TO POLISH THE FLOOR WITH THEIR POLISHING MACHINES, NO. JUST BECAUSE THE LIGHTS ARE OUT, THERE'S NOBODY HOME, THAT POLISHING MACHINE WILL GET SWEPT INTO THE MAGNET AND DAMAGE THE MAGNET AND DAMAGE THE POLISHING MACHINE. THEN THERE'S SOME METALLIC IMPLANTING DEVICES IN PATIENT S SUCH AS PACEMAKER, COCHLEAR IMPLANTS THAT WILL BE RUINED, YOU DON'T WANT TO BRING PATIENTS WITH THOSE IN. INCREASINGLY PATIENTS ARE MR COMPATIBLE, EVEN SOME COCHLEAR IMPLANTS ARE MR COMPATIBLE, SO IT CAN BE DONE. BUT YOU NEED TO REALLY LOOK INTO WHAT THE PATIENT HAS INSIDE THEIR BODY. SO LET'S DO A LITTLE PHYSICS OF HOW THIS ALL WORKS. IT'S SORT OF MAGIC. HOW DOES A MAGNETIC FIELD CREATE AN IMAGE THAT YOU CAN USE IN DIAGNOSE -- IN MEDICINE? SO IF YOU TAKE PROTONS, YOU KNOW, MOST OF WHICH ARE INVOLVED WITH WATER MOLECULES, H2O, EACH H IS A PROTON, THEY ARE RANDOMLY DISTRIBUTED IN SPACE. THERE'S NO PARTICULAR ORDER TO THEM. BUT THEN YOU APPLY A MAGNETIC FIELD AND LIKE SOLDIERS THEY WILL COME TO ATTENTION AND ALIGN EITHER WITH OR AGAINST THE MAGNETIC FIELD. SLIGHTLY MORE WITH THAN AGAINST, BUT STILL THERE'S A BALANCE. AND SOME VERY SMART PHYSICISTS UNDERSTOOD OR DISCOVERED THAT IF YOU TAKE THESE LITTLE SOLDIERS THAT ARE ALIGNED WITH MAGNETIC FIELD AND APPLY A RADIO FREQUENCY, RADIO FREQUENCY WAVE, THAT IS LIKE RADIO, AT A SPECIFIC FREQUENCY, YOU CAN GET THESE SPINS TO DEVIATE FROM THEIR ALIGNMENT WITH THE MAGNETIC FIELD TEMPORARILY. YOU CAN GET THEM TO POINT IN ANOTHER DIRECTION. AND WHEN YOU TURN OFF THE RF, THEY RELAX BACK TO THE NATIVE STATE AND WHEN THIS WHEN THEY DO THAT IF YOU HAVE A RADIOFREQUENCY COIL YOU CAN DETECT SIGNAL AS IT RELAXES BACK. IT APPLIES RF PULSE WHICH DEVIATES THE SPINS INTO, SAY, ANOTHER PLANE, AND THAT'S CALLED -- FIT GOES INTO THIS PLANE 90-DEGREE PULSE OR IF IT GOES ALL THE WAY IN THE OPPOSITE DIRECTION THAT'S 180-DEGREE PULSE SO YOU CAN DESIGN VERY COOL PULSES EITHER 180 OR 90, AS YOU CAN SEE, AND THEN YOU APPLY, AND THIS IS THE REAL MAGIC, GRADIENTS, MAGNETIC GRADIENTS AT THE SAME TIME OVER THE PATIENT SO EACH SITE IN THE BODY HAS ITS OWN UNIQUE RESONANCE FREQUENCY. THAT WAY YOU CAN RESOLVE WHERE YOU ARE BECAUSE YOU KNOW AT THIS LOCATION ONLY THESE SPINS WILL BE GIVING YOU SIGNAL, AT THIS LOCATION ONLY THESE SPINS. AND SO PAINSTAKINGLY YOU CAN WORK THROUGH THAT WHOLE THING, AND GENERATE ENOUGH SIGNAL TO CREATE AN IMAGE. AND, AGAIN, IT'S A LITTLE MORE COMPLICATED. I NOTICED SOMEONE WHO KNOWS SOMETHING ABOUT THIS IN THE ROOM SO I'M HESITANT TO GO INTO TOO MUCH DETAIL BUT SUFFICE IT TO SAY THAT YOU CAN TAKE THESE SIGNALS AND SORT OF BACK-PROJECT THEM IN A WAY AND RECREATE THE -- YOU KNOW, WHAT'S IN THE CENTER OF THE MAGNET. YOU DO THIS ITERATIVELY OVER AND OVER AGAIN AND EVENTUALLY YOU GET A VERY NICE IMAGE. SO WHAT ARE SOME OF THE DETAILS OR LOOKING UNDER THE HOOD OF AN MRI? SO LIKE ALL THESE SCANNERS THERE'S A GANTRY, AND THE PATIENT OBVIOUSLY IS LYING IN HERE. NOW, IF YOU'VE EVER HAD AN MRI YOU HEAR A CLUNKING NOISE THAT'S VERY LOUD BECAUSE OF THE MOVEMENT OF THE GRADIENT COILS AS THE GRADIENTS ARE APPLIED, THEY MOVE A LITTLE BIT. THE MOVEMENT CAUSES A BIG CLUNK THAT YOU HEAR. THAT'S WHY WE HAVE TO USE EAR PROTECTION FOR THE PATIENTS WHO ARE IN THERE. SO WE PUT HEAD PHONES OVER AND ALSO DO A NUMBER OF THINGS TO TRY TO PROTECT THE EARS. SO ONE OF THE KEY THINGS TO GETTING THE MAGNETIC FIELD UP TO THE HIGH LEVELS THAT WE NEED IT TO GET IS TO HAVE SUPER CONDUCTING WIRE WHICH IS IN A BED OF LIQUID HELIUM, SO IT'S SOAKING IN LIQUID HELIUM OR IF THERE'S A PACKAGING AROUND IT OF LIQUID HELIUM, AND WHEN YOU BRING WIRES DOWN TO THAT TEMPERATURE, YOU CAN APPLY AN ELECTRICAL CURRENT AND IT WILL CONTINUE AND CONTINUE. NO RESISTANCE. SO YOU CHARGE UP THE MAGNET AND REALLY DON'T HAVE TO POWER IT OR ADD MORE POWER, UNLESS YOU START RUNNING OUT OF LIQUID HELIUM. SO THAT MAKES IT VERY EFFICIENT IN TERMS OF USAGE OF POWER. IF YOU WERE TRYING TO ACHIEVE HIGH MAGNETIC FIELDS WITH RESISTIVE MAGNET, ELECTRO MAGET, YOU'D HAVE TO GET A POWER PLANT THE SIZE OF ONE THAT TAKES CARE OF BETHESDA TO DO ONE MRI. BUT RATHER THIS BECOMES MUCH MORE EFFICIENT. YOU CHARGE IT UP. IT DOES TAKE A LOT OF ENERGY TO CHARGE UP, YOU CHARGE UP AND THEN YOU JUST KEEP IT GOING WITH THE SUPER CONDUCTING MAGNET. THAT CREATES A LITTLE BIT OF DANGER BECAUSE IF SOMETHING GOES WRONG LIKE THERE'S A SHORT IN THE WIRE OR SOMETHING ELSE HAPPENS, BOIL-OFF OF LIQUID HELIUM, ALL THIS ENERGY IS CONVERTED INTO HEAT VERY RAPIDLY. AND THE HEAT TAKES THIS LIQUID HELIUM AND TURNS IT INTO GASEOUS HELIUM RIGHT AWAY. LIQUID HELIUM IS A VERY, VERY LOW TEMPERATURE, AND SO IF YOU START GENERATING HEAT, IT TURNS IT FROM LIQUID TO GAS. AND A GAS HAS TO GO SOMEWHERE. AND SO IF YOU DON'T VENT THE SCANNER OUT TO THE OUTSIDE, ALL THAT HELIUM GAS IS GOING TO FILL UP THE ROOM WHERE THE MRI IS, AND IT'S GOING TO DISPLACE THE OXYGEN. AND THEY LEARNED THE HARD WAY THAT PATIENTS WON'T BE ABLE TO BREATHE. SO YOU HAVE TO QUICKLY VENT ANY ESCAPED GAS OUTSIDE THE ROOM, OUTSIDE THE BUILDING. YOU ALWAYS SEE WHEN YOU LOOK AT AN MRI, THIS BIT THAT'S CONNECTED TO THE CEILING, AND THAT'S THE SO-CALLED QUENCH PIPE, WHERE IN THE EVENT OF A CATASTROPHE, THE GAS WILL BE VENTED OUT OF THE ROOM AND NOT INTO THE PATIENT. SO THERE'S ALSO AN INJECTOR LIKE WITH CT, SIMILAR, OPERATES IN A SIMILAR WAY. THERE'S EAR PROTECTION DEVICE I TALKED ABOUT. SO JUST A WORD ABOUT SAFETY. SO ORDINARY OBJECTS LIKE KEYS, SCISSORS, ANY KIND OF TOOLS CAN BE RAPIDLY SUCKED INTO THE MAGNET. SO WE DESIGNED THESE ROOMS SO THERE'S SO-CALLED DIFFERENT ZONES WHERE THE DRESSING ROOM, YOU DON'T HAVE TO BE VERY CONCERNED ABOUT IT BECAUSE YOU'RE NOT VERY CLOSE TO THE MAGNET. AS YOU ENTER THE NEXT ZONE, ZONE 3, THE CONTROL ROOM, YOU'RE ABOUT TO GO INTO THE SCANNER, THERE'S A PROCESS IN PLACE WHEREBY YOU'RE CHECKED FOR ANY OF THESE KINDS OF OBJECTS, YOUR HISTORY IS TAKEN, AND IT'S MADE CLEAR THAT YOU'RE SAFE TO GO IN. THEN ZONE 4 IS WHERE THE MAGNET IS. THERE'S A DESIGN -- A PURPOSEFUL DESIGN TO MAKE SURE THIS IS SAFE. SO FROM EARLY DAYS OF MR, THERE'S OUR BUFFER, WHERE IT SHOULDN'T BE, AND HERE'S A CABINET, AND THESE ARE VERY, VERY PAINFUL EXPERIENCES, I CAN TELL YOU, BECAUSE THE MAGNET IS VERY DAMAGED, IT TAKES A LOT OF WORK TO REMOVE THESE THINGS, AND IT'S EXPENSIVE, AND JUST CAN BE AVOIDED. HERE'S AN OXYGEN TANK THAT'S BEEN SUCKED INTO THE MAGNET. YOU CAN IMAGINE IF THERE WAS SOMEBODY'S HEAD, IT COULD HAVE BEEN A CATASTROPHE, IT'S AN AIRBORNE TOWARD. -- TORPEDO. WE TAKE THE WARNINGS SERIOUSLY. SO LIKE CT, WE ALSO USED CONTRAST MEDIA FOR MRI. AND YOU CAN LIGHT UP LIKE THIS TUMOR HERE USING GADALINIUM, A PARAMAGNETIC SUBSTANCE THAT IN A MAGNETIC FIELD WILL INFLUENCE FIELDS OF ADJACENT SPINS. SO YOU HAVE THESE DIFFERENT TYPES OF GADALINIUM COMPOUNDS, LIKE THESE LINEAR COMPOUNDS, AND THESE CYCLIC COMPOUNDS THAT CAPTURE THE GADALINIUM AND KEY THEM IN THE CHELATE. SOME ARE MORE STABLE THAN OTHERS. IF WE LOOK AT THERMODYNAMIC STABILITY CONSTANT, AN EXPONENTIAL TERM, IN OTHER WORDS WHEN I SAY THIS ONE IS 22 AND THIS IS 25, I MEAN IT'S APPROXIMATELY A THOUSAND TIMES MORE STABLE. SO THERE ARE AGENTS THAT ARE EXTREMELY STABLE, THE TOP OF THE HEAP HERE IS GADOTERATE, OR DOTAREM, WHICH IS WHAT WE USE, AND IT'S VERY STABLE. HERE IS ONE THAT'S QUITE GOOD. AND THEN THEY GET LOWER AND LOWER. AND SOME OF THEM ARE REALLY MULTIPLE ORDERS OF MAGNITUDE LOWER IN THERMODYNAMIC STABILITY, AND THAT MEANS THE GADALINIUM WHICH SHOULD BE CAPTURED IN THE MOLECULE BECOMES LOOSE. GADALINIUM IS AN EXTREMELY TOXIC ATOM, AND IN PATIENTS WHO HAVE VERY POOR RENAL CLEARANCE YOU CAN GET A SYNDROME CALLED NEPHROGENIC SCLEROSIS, GADALINIUM IN THE SOFT TISSUES LEADS TO SEVERE FIBROSIS, IN THIS CASE IT'S DIFFICULT FOR THE PATIENT TO BEND THEIR FINGERS OR BEND THEIR KNEE, AND IT CAN BE A FATAL ILLNESS. FORTUNATELY, IF YOU DON'T GIVE GADALINIUM TO PATIENTS WITH RENAL FAILURE OR VERY POOR RENAL FUNCTION YOU CAN AVOID THIS DISEASE. AND SINCE ITS DISCOVERY IN 2007, ITS RECOGNITION, THE NUMBER OF CASES HAS PLUMMETED DRAMATICALLY. SO THE GADALINIUM MOLECULE IS VERY -- IS HIGHLY TOXIC, BUT PATIENTS WITH NORMAL RENAL FUNCTION EXCRETE THE GADALINIUM CHELATES VERY RAPIDLY, CERTAINLY WITHIN 24-48 HOURS. IT'S REALLY PATIENTS WITH ABNORMAL RENAL FUNCTION THAT MAY TAKE WEEKS TO EXCRETE THE AGENT AND DURING THAT TIME SOME LESS SECURE GADALINIUM CHELATES WILL ALLOW DISASSOCIATION OF GADALINIUM, WHICH CAN THEN DEPOSIT IN SOFT TISSUES. AND THAT CAN LEAD TO FIBROSIS. SO THE RISK FACTORS ARE RENAL FAILURE, HOW MUCH DOSE YOU'RE GIVING CLEARLY, WHICH AGENT YOU'RE GIVING, THE MORE STABLE ONES THE BETTER. AND ALWAYS IT'S IMPORTANT TO CONSIDER ALTERNATE ALTERNATIVE IMAGING FOR THOSE TYPES OF PATIENTS, A CT OR PET SCAN MIGHT DO AS WELL, OR A NON-CONTRAST MRI WILL ANSWER THE QUESTION SO YOU DON'T NEED TO PUT THE PATIENT AT RISK. NOW, RECENTLY, THERE'S BEEN A LOT OF CONCERN ACROSS THE WORLD ABOUT AN OBSERVATION THAT'S BEING MADE THAT PATIENTS WHO RECEIVE GADALINIUM, ESPECIALLY MULTIPLE DOSES SHOW AN ACCUMULATION IN PARTS OF THE BRAIN. NOW IT'S NOT ASSOCIATED YESTERDAY WITH ANY KNOWN SYMPTOMS OR SIGNS OR PREMATURE DEATH OR ANYTHING, BUT THERE IS THIS CONCERN I WOULD SAY, DEPOSITION OF GADALINIUM, PRESUMABLY FREE GADALINIUM BUT NOT CLEAR, IN PARTS OF THE BRAIN. EUROPEAN REGULATORY AGENCY HAS ACTUALLY STARTED TO BAN SOME OF THESE LOWER THERMO -- LESS STABLE COMPOUNDS, ONLY PERMITTING MORE STABLE COMPOUNDS. USDA HAS LOOKED AT THE DATA, SAID IT'S TRUE IT'S DEPOSITING BUT WE CAN'T SHOW HARM SO THEY ARE NOT PUTTING RESTRICTIONS ON AGENTS. WE'VE MADE OUR OWN DECISION THAT WE'RE GOING TO USE THE MOST STABLE GADALINIUM CHELATE THERE IS, AND TRY TO DECREASE THE AMOUNT OF DEPOSITION. LET'S MOVE TO ULTRASOUND, ALWAYS THE FUNNEST MODALITY, BECAUSE YOU CAN STAY IN THE ROOM, THERE ARE NO PROJECTILES, THERE'S& NOTHING DANGEROUS. IT'S VERY SAFE. IT'S USUALLY DONE IN HAPPY CIRCUMSTANCES LIKE OBSTETRICAL IMAGING. SO IT'S NO RADIATION. IT'S REAL TIME, UNBELIEVABLE. PICK UP THE PROBE, THE ULTRASOUND PROBE, PUT IT ON THE PATIENT AND SEE IMAGES RIGHT AWAY. NO PROCESSING, NO RECONSTRUCTION. VERY INEXPENSIVE. IT'S CERTAINLY THE MOST COMMON MODALITY ACROSS THE WORLD, NO PREP, NO INJECTION. WHAT'S NOT TO LIKE ABOUT ULTRAOUND? SO THERE ARE SOME PROBLEMS WITH IT. FIRST OF ALL, IT REALLY MATTERS WHO IS HOLDING THE PROBE. YOU NEED TO BE A SKILLED USER. YOU CAN'T BE AN AMATEUR AND GET DECENT IMAGES. AND THE OTHER THING IS THAT IT'S ALMOST LIKE A FLASHLIGHT WHERE YOU PUT THE BEAM, YOU'LL SEE SOMETHING. IF YOU DON'T PUT THE BEAM, IN A CERTAIN AREA, YOU WON'T SEE IT. SO YOU HAVE TO HAVE SORT OF COMPLETENESS OF SCANNING, IN ORDER TO MAKE SURE THAT YOU COVER EVERYTHING. SO WHAT YOU SEE IS ALL THERE IS. IF YOU DON'T SCAN THE PATHOLOGY, YOU WON'T SEE THE PATHOLOGY. UNLIKE CT, YOU GET EVERYTHING. SO IT'S VERY DIFFICULT TO QUANTIFY. WE CAN MEASURE ON MRI, WE CAN MEASURE ON CT BUT ULTRASOUND IS VERY DIFFICULT DO MEASURE. THEN THERE ARE PARTS OF THE BODY THAT WON'T TRANSMIT SOUND. SO AIR DOESN'T TRANSMIT SOUND. SO THE LUNGS, YOU CAN'T SEE ANYTHING. BONES, THE SOUND JUST BOUNCES OFF BONES. CAN'T SEE ANYTHING. THE BRAIN, BECAUSE IT'S SURROUNDED BY BONE, YOU CAN'T SEE ANYTHING. NOW, IN THE OPERATING ROOM, WHEN THE SKULL IS OPEN, YOU CAN GET AN ULTRASOUND PROBE AND SEE ALL KINDS OF THINGS IN THE BRAIN, BUT THROUGH THE HAIR AND THE BONE YOU REALLY CAN'T SEE ANYTHING. SO THIS IS REALLY PRETTY SIMPLE. THE PRINCIPLE OF ULTRASOUND, YOU SEND OUT A HIGH FREQUENCY SHOCK WAVE, SOUND WAVE. THAT'S WHAT A SOUND WAVE IS. IT'S A SERIES OF SHOCKS. THIS IS, AT, SAY 5 MEGAHERTZ, A MILLION CYCLES PER SECOND, REALLY MOVING FAST. AND YOU SEND THOSE OUT. AND THEY WILL HIT AN OBJECT AND THAT WILL REFLECT BACK AND IF YOU'RE SMART, LIKE THE PEOPLE WHO BUILT THESE SCANNERS, YOU KNOW THAT IN TISSUE, SOUND HAS A SPECIFIC SPEED, SO IF YOU SEND OUT A PULSE AND YOU WAIT, AND YOU COUNT HOW MUCH TIME IT TAKES TO GET BACK, YOU KNOW HOW DEEP THAT THING IS RIGHT AWAY BECAUSE YOU CAN TELL BY THE TRAVEL TIME. SO YOU CAN START TO LOCALIZE THINGS BY HOW LONG IT TAKES TO GET THE SOUND BACK. SO SOUND CAN DO A BUNCH OF THINGS IN THE BODY. IT CAN BE COMPLETELY ATTENUATED. SO FOR INSTANCE IF THIS IS THE SKIN AND YOU SEND OUT AN ULTRASOUND BEAM AND YOU ENCOUNTER AIR IN THE LUNG, BOOM, STOP. THAT'S ALL YOU'RE GOING TO SEE. SO THAT'S ATTENUATION. THEN THERE'S ABSORPTION WHICH IS THE NORMAL THING SO AS YOU GO DEEPER IN THE TISSUE, THERE'S ABSORPTION OF THE SOUND. SO THE SIGNAL GETS LESS AND LESS AND LESS. BUT THE ENGINEERS ARE VERY SMART. THEY KNOW THAT. SO THEY KNOW THAT THE LONGER DISTANCE YOU NEED TO TRAVEL WITH THE SOUND, YOU NEED TO AMPLIFY IT A LITTLE BIT. THE DEEPER YOU AMPLIFY MORE. SO THIS IS CALLED A TIME GAIN SETTING. LONGER THE TIME, THE MORE THE GAIN. YOU CAN CORRECT FOR THAT. THAT'S REFLECTION, THAT'S OBVIOUS, SOMETHING THAT'S LIKE A STONE WILL BE VERY REFLECTIVE BECAUSE IT'S A BIG IMPEDENCE MISMATCH BETWEEN THE TISSUE AND STONE AND WILL SEND THE WAVE BACK. IT CAN SCATTER THE SOUND IN DIFFERENT DIRECTIONS. IT CAN REFRACT LIKE LIGHT AND IT CAN DEFRACT. THAT'S WHERE YOU GET STRANGE ARTIFACTS THAT ULTRASOUND GUYS LOVE TO SHOW. CAN YOU DO A LOT WITH ULTRASOUND. THIS IS A PATIENT WHO HAS LOTS OF SPOTS IN THEIR LIVER. UNFORTUNATELY IT'S METASTATIC DISEASE BUT YOU CAN REALLY VERY INSTANTLY TELL WHAT'S GOING ON THERE. SO THERE'S A LITTLE MAGIC TO THESE PROBES. IN FACT, I DON'T HAVE A SLIDE BUT THEY HAVE ACTUALLY GONE TO WIRELESS PROBES NOW SO YOU DON'T HAVE WIRES. BUT THERE'S A PIEZO ELECTRIC CRYSTAL IN THIS THING TO WHICH YOU APPLY A HIGH FREQUENCY CURRENT, AROUND THAT WILL CAUSE THAT CRYSTAL TO VIBRATE, THAT VIBRATION GETS SENT FORTH THROUGH -- HERE'S THE PIEZEELECTRIC, IT GETS SENT THROUGH THE FREQUENCY. CAN YOU HAVE SHAPES, INTRACAVITARY PROBES. THIS IS OUR STAND AROUND IN-HOSPITAL SCANNER, THEY ARE GORGEOUS DEVICES. IT'S AMAZING WHAT YOU CAN SEE WITH THEM. BUT MINIATURIZATION IS HAPPENING, AND THIS IS A SCANNER THAT WE HAVE CALLED SONOSITE, BASICALLY A LAP TOP WITH A PROBE, AND THEN OF COURSE EVERYTHING GETS CONNECTED TO A PHONE, SO THERE ARE PHONE-SIZE ULTRASOUND DEVICES NOW. SO IT'S VERY INCREDIBLE. ONE OF THE GREAT THINGS OF COURSE ABOUT ULTRASOUND IS THE REALTIME ASPECT, AND THAT BECOMES VERY IMPORTANT WHEN YOU'RE TRYING TO DO A PROCEDURE LIKE A BIOPSY. SO YOU CAN USE THE ULTRASOUND, GET REALTIME IMAGES AND WATCH THE NEEDLE GO INTO THE THING YOU'RE TRYING TO BIOPSY SO THAT'S MUCH BETTER THAN CT WHERE YOU HAVE TO PUT THE NEEDLE IN, SCAN, SEE WHERE IT IS, MOVE THE NEEDLE SOME MORE, SCAN, SEE WHERE IT IS. THIS IS REAL TIME. SO IT'S ADVANTAGEOUS. LAST THING I WANT TO TALK ABOUT ULTRASOUND IS CONTRAST AGENT, WHICH IS VERY DIFFERENT FROM THE OTHER CONTRAST AGENTS, SMALL MOLECULES. THESE ARE GIANT MOLECULES REALLY, BUBBLES, FILLED WITH GAS. AND BECAUSE THEY ARE FILLED WITH GAS, THEY REFLECT A LOT. YOU KNOW, JUST LIKE I SAID, AIR REFLECTS A LOT. THIS GAS REFLECTS A LOT. IT ACTUALLY CAUSES REVERBERATIONS OF THE SOUND THAT YOU CAN PICK UP. YOU CAN ACTUALLY CRUSH THESE MICRO BUBBLES AND RELEASE WHATEVER IS IN THEM. SO PEOPLE ARE USING THAT FOR DRUG DELIVERY, SO YOU CAN SEE THE MICROBUBBLE GET INTO THE ORGAN AND INCREASE THE POWER AND CRUSH THE BUBBLE AND ALL THE DRUG COMES OUT RIGHT WHERE YOU WANT IT. SO THAT'S A NEW TECHNOLOGY. SO THE LAST FEW MINUTES WHAT I WANT TO MOVE ON TO ARE A FIELD CALLED NUCLEAR MEDICINE WHICH IS ALLIED WITH CT, MRI AND ULTRASOUND BUT IT'S FUNDAMENTALLY DIFFERENT IN THAT IT INVOLVES THE INJECTION OF A RADIOACTIVE SUBSTANCE INTO THE BODY. SMALL AMOUNTS. SO LET'S JUST DO SOME BASICS OF ATOMIC PARTICLES. THE BIGGEST ONE THAT'S EMITTED FROM A NUCLEUS IS AN ALPHA PARTICLE, WHICH IS A HELIUM NUCLEUS. AND THAT'S A PRETTY BIG BOWLING BALL. IT HAS A LOT OF ENERGY BUT IT DOESN'T GET VERY FAR. IN FACT, A SHEET OF PAPER WILL BLOCK AN ALPHA PARTICLE. SO IT'S NOT REALLY THAT USEFUL FOR IMAGING. IT'S NOT GOING TO GET ANYWHERE. A BETA PARTICLE WHICH IS AN ELECTRON, A CHARGED ELECTRON, CAN GET THROUGH A LITTLE BIT DEEPER, BUT IT IS ALSO -- IT HAS LIMITATIONS TO THE SORT OF MILLIMETER RANGE. AND THEN THERE'S THE GAMMA RAY, WHICH IS THE COUSIN OF THE X-RAY, VERY HIGH ENERGY, IT'S A PHOTON, DOESN'T REALLY HAVE MASS, PER SE, ALTHOUGH EINSTEIN WOULD YELL AT ME FOR THAT. AND SO IT ACTUALLY PENETRATES VERY FAR. SO WE'RE GOING TO BE TALKING ABOUT RADIOACTIVE MATERIALS THAT RELEASE GAMMA RAYS, SO CALLED SINGLE-PHOTON EMISSIONS. SO THEN WE'RE GOING TO CAPTURE THAT ON WHAT LOOKS PRETTY MUCH LIKE A CT, BUT IT'S A LITTLE BIT DIFFERENT. SO WE'LL TALK ABOUT THAT. SO, THE ADVANTAGE OF A SPECT SCANNER, THE AGENTS ARE RELATIVELY INEXPENSIVE. IT'S A TECHNOLOGY THAT'S BEEN AROUND FOR MANY, MANY YEARS. BUT IT DOES INVOLVE RADIATION, THERE'S PREPARATION OF THIS IMAGING AGENT, THERE ARE A LOT OF NUCLEAR REGULATORY ISSUES, AND THE SCANNING IS EXTREMELY SLOW. IT CAN TAKE AN HOUR TO SCAN A PATIENT. AND THE RESOLUTION IS EVEN WORSE, AT 6 TO 7 MILLIMETERS RESOLUTION. AND WHAT GOES ON IS THAT YOU HAVE A SOURCE OF GAMMA RAYS, LET'S SAY THIS IS IN THE BODY, THERE'S SOMETHING THAT YOU'VE INJECTED, RADIONUCLEI TECHNESIUM AGENT, IT EMITS IN EVERY DIRECTION, DOESN'T KNOW WHERE THE SCANNER IS, EMITS SCANNERS WILLY-NILLY. YOU NEED TO CORRAL THE GAMMA RAYS IN A CERTAIN WAY SO YOU HAVE SOME IDEA WHERE THEY ARE COMING FROM. THE WAY DO YOU THAT IS WITH SOMETHING CALLED A COLLIMATOR, IT PUTS INTO COLUMNS THE GAMMA RAYS, IF THEY DON'T GO THROUGH THE HOLES YOU DON'T SEE THEM. THEY ARE REJECTED IN THE TERMINOLOGY. AND THEN ONLY THE ONES THAT GET THROUGH ARE ALLOWED TO HIT THIS CRYSTAL, WHICH SCINTILLATES, AND THE LIGHT IS DETECTED. THAT'S THE WAY IT WORKS. YOU CAN SEE BECAUSE OF THE COLLIMATOR YOU'RE REFLECTING A LOT OF THE RADIOACTIVITY, SO THE PATIENT IS GETTING ALL THIS RADIOACTIVITY BUT ONLY A TINY PERCENT, LESS THAN 1% OF IT IS CAPTURED FOR IMAGING. SO THIS IS A PICTURE OF A COLLIMATOR. YOU CAN SEE IT'S USUALLY MADE OUT OF SOME VERY DENSE MATERIAL LIKE TUNGSTEN, AND THE GAMMA RAY HAS TO MAKE IT RIGHT DOWN THE CENTER OF THAT THING, OTHERWISE IT'S GOING TO GET REJECTED, IF IT COMES IN AT THE SIDE IT WILL GET REJECTED. SO IT MAKES IT RELATIVELY INEFFICIENT. SO WE IN THIS CASE HAVE A TECHNETIUM METHYL DIPHOSPHONATE THAT GOES TO BONES, TURNING OVER AND GROWING. HERE IS A POSITIVE BONE SCAN WITH MULTIPLE METASTATIC LESIONS, AND THIS AGENT, 99M TECHNETIUM HAS A 6 HOUR HALF-LIFE, BY 24 HOURS IT'S NEGLIGIBLE AMOUNT OF ACTIVITY, YOU HAVE A FEW HOURS TO SCAN THE PATIENT AFTER YOU'VE INJECTED THEM. THERE ARE A BUNCH OF AGENTS THAT ARE AVAILABLE FOR SPECIFIC USES, LIKE FOR A THYROID AND SALIVARY GLAND IMAGING, WE USE PERTECHNETATE TO LIKE AT THYROID WE USE THAT WILL YUM, INDIUM FOR WHITE CELL LABELING, DIFFERENT AGENTS FOR DIFFERENT PARTS OF THE BODY. WHAT WE CAN NOW ADD IN ADDITION TO THE SINGLE PHOTON CAPTURE, WHICH IS THIS PART OF THE DEVICE, CAN YOU ADD CONVENTIONAL CT, GET BOTH IMAGES AND SUPERIMPOSE THEM ON EACH OTHER. HERE IS A PATIENT WITH HEAD AND NECK CANCER, THEY HAVE NODES LIGHTING UP, AND YOU CAN SEE THAT SUPERIMPOSED ON THE CT SCAN, THAT'S OBTAINED AT THE SAME TIME. THAT'S HYBRID IMAGING, TWO TECHNIQUES INTO ONE. SO THE LAST TOPIC IS POSITRON EMISSION TOMOGRAPHY, PROBABLY THE COOLEST PART OF THE DEPARTMENT. SO POSITRONS ARE ACTUALLY POSITIVE ELECTRONS. THEY ARE IN THE GENERAL CLASS OF ANTI-MATTER, WHICH ACTUALLY EXISTS. AND POSITRONS ARE EMITTED BY SPECIFIC KINDS OF RADIOACTIVE MATERIALS. THEY COME OUT AND THEN THEY MEET AN ELECTRON, AND AN EVENT HAPPENS, ANNIHILATION, SO MATTER MEETS ANTI-MATTER, AND TURNS INTO ENERGY. IN A VERY SPECIFIC WAY. TWO GAMMA RAYS OF 511 KEV EACH ARE EJECTED IN OPPOSITE DIRECTIONS. AND THAT MAKES ALL THE DIFFERENCE IN THE WORLD COMPARED TO SPECT, SPECT REMEMBER THE EVENTS ARE HAPPENING IN RANDOM DIRECTIONS, IN PET THEY ARE HAPPENING IN A VERY PRESCRIBED WAY. OPPOSITE DIRECTIONS TO EACH OTHER. SO, IF YOU SEE AN EVENT HERE, AND AN EVENT HERE, AT THE SAME TIME, YOU KNOW THAT SOMEWHERE ALONG THAT LINE THERE'S AN EVENT THAT HAPPENED. THERE'S A RADIOACTIVE DECAY THAT OCCURRED. AND IF YOU DO THAT ENOUGH, YOU COLLECT THAT ENOUGH, YOU CAN COMPOSE AN IMAGE WITH MUCH BETTER RESOLUTION THAN THE SPECT, BUT VERY HIGHLY SENSITIVE. SO YOU CAN GET HIGHLY SENSITIVE SCAN, YOU CAN GET METABOLIC INFORMATION, BECAUSE YOU CAN ACTUALLY SEE AGENTS THAT ARE TAKEN UP IN SPECIFIC METABOLIC SITUATIONS. THE SPATIAL RESOLUTION IS IMPROVED. AND IT IS ALSO COMBINED WITH CT, HYBRID APPROACH. IT'S EXPENSIVE. IT HAS THE SAME REGULATORY ISSUES AND HALF-LIFE IS SHORT SO YOU GOT TO GET ON IT. SO JUST TO REVIEW, THIS ONE OF OUR WORK HORSE ISOTOPES FOR PET, F18, EMITS A POSITIVE ELECTRON OR POSITRON, AND IT GOES SOME DISTANCE WHICH IS GOVERNED BY THE ENERGY OF THE POSITRON, AWAY FROM THE NUCLEUS, AND THEN IT MEETS AN ELECTRON, ANNIHILATES, AND TWO GAMMA RAYS ARE EMITTED, OPPOSITE EACH OTHER, AT 511 KEV, VERY PRECISE, ALWAYS THE SAME AMOUNT OF ENERGY, NO MATTER THE ISOTOPE THE ENERGY IS ALWAYS 511 KV. YOU CAN GET BETTER SPATIAL RESOLUTION. SENSITIVE IS IN THE PICOMOLAR RANGE. IN THE '20s, OTTO WARBURG FIGURED OUT CANCERS MAKE A SWITCH, INSTEAD OF GLUCOSE IN AN AEROBIC WAY, USES IT ANAEROBICALLY. BECAUSE IT'S MUCH LESS EFFICIENT THAN GLUCOSE UPTAKE IS MUCH LESS EFFICIENT WHEN YOU DO IT ANAEROBICALLY YOU NEED MORE GLUCOSE, TUMORS BECOME AVID FOR GLUCOSE. FAST FORWARD 30 YEARS, 40 YEARS, AND A SCIENTIST HERE AT THE NIH, LOU SOKOLOFF, HAD THE IDEA OF MAKING ARTIFICIAL GLUCOSE, FLUORODIE OXY GLUCOSE, THE BODY TREATS THAT LIKE GLUCOSE BUT TRAMS TRAPS IT RATHER THAN CONTINUING TO PROCESS AS IT WOULD WITH GLUCOSE. HE DIDN'T SEE THE FULL POTENTIAL BUT THAT LED TO THE DEVELOPMENT OF F18 FDG, WHICH WAS A LABELED VERSION OF IT THAT WE COULD DETECT AND THEREFORE LOOK AT METABOLISM, WITH PET SCAN. SO HERE, FOR INSTANCE, IS A PET SCAN THAT USES FDG, AND I WANT TO POINT OUT A FEW THINGS ABOUT THIS. SO BASICALLY WHAT'S GOING ON IS THE FDG IS INCORPORATED INTO THE CELL, PHOSPHORYLATED, BUT IT'S TRAPPED INSIDE THE CELL. SO IT CAN'T GET OUT. SO HERE IT IS THE MOLECULE COMING INTO THE CELL, THROUGH THE GLUT TRANSPORTER, TRAPS IN THE CELL SO IT ACCUMULATES. WHERE DOES IT ACCUMULATE? WELL, ACCUMULATES IN THE BRAIN, IT ACCUMULATES IN THE HEART, IT ACCUMULATES IN THE KIDNEY BECAUSE IT'S EXCRETED BY THE KIDNEY BECAUSE IT'S NOT REALLY GLUCOSE. YOU KNOW, REGULAR GLUCOSE ISN'T EXCRETED MUCH IN THE KIDNEY BUT THIS IS FAKE GLUCOSE SO THE KIDNEY MIRACULOUSLY TO ME IS ABLE TO IDENTIFY IT AS FAKE, SAYS I'M GOING TO EXCRETE YOU, EXCRETES IT INTO THE BLADDER AS YOU CAN SEE HERE. THIS IS A MALE, TESTICLES ARE LIGHTING UP. WHY? THEY ARE METABOLIC. THE LIVER AND SPLEEN PRETTY METABOLIC. AND THESE ARE THE TONSILS AROUND THE RING OF WALLDIRE, FAIRLY ACTIVE. MAYBE HE HAS A COLD OR SOMETHING THAT'S ACTIVATING THAT. SO YOU CAN SEE ALL THESE THINGS, AND OF COURSE TUMORS SHOW UP AS WELL. SO HERE'S A TUMOR, A PATIENT WITH METASTASES, AND HERE FOR INSTANCE IS UPTAKE IN THE SINUSES, UPTAKE IN THE RIB, THERE THE ILIAC BONE, AND YOU CAN CORRELATE THAT WITH THE BONES, THE BONES LOOK VERY ABNORMAL IN THIS SITUATION. AND HERE'S ANOTHER EXAMPLE. THIS IS A PATIENT WITH BREAST CANCER, AND YOU CAN SEE THE CT SCAN SHOWS A LOT OF ABNORMALITIES, THERE'S THIS BIG THING OCCUPYING MOST OF THE CAVITY, BUT IF YOU LOOK AT THE PET CT IT TELLS YOU THIS IS A TUMOR, THIS IS A TUMOR, AND THIS IS JUST FLUID. THERE'S NOTHING METABOLICALLY ACTIVE GOING ON THERE ON THE OTHER HAND, WHEN YOU LOOK AT THIS SAGITTAL VIEW YOU CAN SEE SOME OF THE VERTEBRAL BODIES ARE ACTIVE, METASTASIS THERE. IT'S AN EXTREMELY POWERFUL TECHNIQUE THAT ENABLES YOU TO SEE ALL KINDS OF THINGS. AND THAT'S JUST FDG. THERE'S A HUGE AMOUNT OF CHEMISTRY THAT'S AVAILABLE TO LOOK AT SPECIFIC THINGS. AND MY LAB IS VERY INTERESTED IN THESE THINGS. SO ONE OF THEM IS SODIUM FLUORIDE THAT PICKS UP IN THE BONE, FLUOROTHYMIDINE, A NUCLEOSIDE, YOU CAN MEASURE CELLULAR PROLIFERATION. ESTRADIOL, FLUOROCHOLINE, MEMBRANE TURNOVER. FLUOROMISO FOR HYPOXIA. ONE THAT'S INTERESTING IS FLORBETABEN FOR AMYLOID DETECTION IN ALZHEIMER'S DISEASE. YOU CAN LABEL ANTIBODIES LIKE HERCEPTIN AND WE'RE CURRENTLY LABELING CELLS AND INJECTING THEM TO SEE WHERE THE CELLS GO, IN THE PATIENT. SO ALL KINDS OF THINGS YOU CAN DO WITH THIS AGENT, WITH THIS MODALITY. SO PET HAS THE ADVANTAGES OF HIGH ENERGY PHOTON IMAGING, HIGH SENSITIVITY, ABILITY TO CORRECT FOR ATTENUATION. NO NEED FOR COLLIMATION. THE RESOLUTION IS STILL THREE TO FOUR MILLIMETERS BUT IT'S MUCH BETTER. LET'S GO OVER SORT OF A COMPARISON OF THESE MODALITIES THAT I'VE TALKED ABOUT FOR 50 MINUTES. LET'S TALK ABOUT RESOLUTION.& IN TERMS OF THE SHARPEST RESOLUTION, CT IS AT THE TOP OF THE HEAP. IT HAS SUBMILLIMETER RESOLUTION. MRI CAN APPROACH IT BUT NOT QUITE. ULTRASOUND IS A LITTLE BIT BETTER. PET IS BETTER THAN SPECT, SPECT IS THE WORSE. IF IT'S RESOLUTION YOU'RE AFTER, THAT IS CAN YOU DEFINE TWO VERY CLOSE STRUCTURES TO EACH OTHER, CT IS THE BEST MODALITY. HOW ABOUT SENSITIVITY? YOU'RE TRYING TO PICK UP SOMETHING IN THE BODY. SO BY FAR, THE HIGHEST SENSITIVITY BY MULTIPLE ORDERS OF MAGNITUDE IS PET. BY ABOUT AN ORDER OF MAGNITUDE SPECT IS BEHIND IT. THEN IT GETS GROSS. THERE'S A REASON WHY YOU HAVE TO INJECT 40 GRAMS OF IODINE TO SEE SOMETHING. IT'S BECAUSE IT'S NOT THAT SENSITIVE FOR THE DETECTION OF IODINE. SO YOU REALLY HAVE TO PUT IN A BOAT LOAD, AND IF YOU WERE TRYING TO MEASURE A RECEPTOR, FOR INSTANCE, WITH 40 GRAMS, YOU'D SATURATE EVERYTHING AROUND. I MEAN, YOU'D SATURATE THE RECEPTOR AND EVERYTHING ELSE. YOU WOULDN'T SEE WHAT YOU'RE LOOKING FOR. BUT WITH A PET SCAN, THE NANOMOLAR CONCENTRATION, YOU CAN LOOK AT DETECTORS LIKE ESTROGEN RECEPTOR ON A TUMOR AND DIFFERENTIATE IT FROM TISSUES THAT DON'T HAVE THE ESTROGEN RECEPTOR. OKAY. SO EVERYTHING HAS ITS PROBLEMS. AND SO NOW WHAT ABOUT COST? WELL, ULTRASOUND IS THE MOST EFFICIENT FROM A COST EFFECTIVE, AND THAT'S WHY IT'S USED ROUTINELY. A FRIEND OF MINE WHO RETIRED DECIDED THAT ONE OF THE MOST USEFUL THINGS HE COULD DO WOULD BE TO FUND A SCHOOL IN AFRICA THAT TEACHES HOW TO USE ULTRASOUND BUT ALSO HOW TO REPAIR ULTRASOUND DEVICES. BECAUSE THE NEAREST REPAIR GUYS IN PARTS OF AFRICA ARE IN EUROPE. SO HE WITH HIS OWN MONEY, HE MADE THIS SCHOOL THAT DID THAT, WON ALL KINDS OF PRIZES, HE DID IT BECAUSE HE THOUGHT THIS WAS THE MOST MEANINGFUL WAY HE COULD LEAVE A LEGACY IN HIS FIELD. CT IS COMING DOWN MORE IN PRICE. IT DEMANDS GOOD POWER. YOU KNOW, A HEALTHY POWER SUPPLY, NOT ONE THAT WOBBLES ALL OVER THE PLACE. AND IT REQUIRES SKILLED REPAIR AND ESPECIALLY THE WAY WE DO THINGS NOW, WHERE NOBODY DIAGNOSES ANYTHING. THEY DO IT REMOTELY AND SEND YOU A BOARD TO PUT IN. THEN SPECT, MRI AND PET IS THE MOST EXPENSIVE. SO WHAT I HOPE I'VE DONE IS SORT OF GIVEN YOU AN OVERVIEW OF WHAT MODERN RADIOLOGY DEPARTMENT IS ABOUT, AND, YOU KNOW, MADE THE POINT THAT THE WORK HORSE FOR ONCOLOGY IS CT, BUT FOR MANY SPECIALTY CANCERS, MRI IS USED THE MOST. ULTRASOUND IS USED FOR BIOPSY AND PROBLEM SOLVING. SPECT IS USED FOR BONE METASTASIS, AND PET CT IS USED TO DETERMINE METABOLIC ACTIVITY. SO THAT'S WHAT I WANTED TO SAY. HERE IS MY E-MAIL. AND OUR WEBSITE, IF YOU'RE INTERESTED. AND I'LL BE HAPPY TO ANSWER ANY QUESTIONS THAT YOU MIGHT HAVE. [APPLAUSE] >> WHAT WOULD BE THE BEST WAY FOR EARLY DETECTION? >> WELL, LET'S NARROW THAT QUESTION DOWN. LET'S SAY BEST WAY FOR EARLY DETECTING OF LUNG CANCER, SO THERE'S ACTUALLY A TRIAL THAT WAS CONDUCTED USING CT, LOW DOSE CT SCANS. AND IN SMOKERS OLDER THAN AGE 50 50 WHO HAD A SIGNIFICANT SMOKING HISTORY, 20 PACK YEARS OR SOMETHING LIKE THAT, USING THOSE CRITERIA THE CT WAS ABLE TO DETECT STAGE 1 CANCERS IN SUFFICIENTLY HIGH NUMBERS THAT THEY CLOSED THE STUDY MULTIPLE YEARS EARLY BECAUSE IT WAS UNFAIR FOR THE CONTROL GROUP THAT DIDN'T HAVE CT. SO NOW THAT'S A ROUTINE TEST FOR SMOKERS OF A CERTAIN AGE WHO HAVE A CERTAIN EXPOSURE HISTORY. BUT YOU'LL SEE AROUND COMPANIES THAT WILL, IN MY VIEW, SORT OF PLAY ON PATIENT'S FEARS OR NORMAL PEOPLE'S FEARS, NOT PATIENTS, TO SCREEN FOR CANCER. THERE'S NOTHING WRONG WITH YOU. YOU DON'T HAVE A RISK FACTOR OF ANY SORT. BUT YOU'RE WORRIED. THERE'S THIS INESCAPABLE LOGIC THAT THEY USE WHICH IS, WELL, IF WE FIND IT EARLY, THEN WE CAN SAVE YOU. AND -- YOU KNOW, EVERYBODY BUYS THAT LOGIC. IT'S NOT TOTALLY TRUE, FIRST OF ALL. BUT MORE PROBLEMATIC IS THAT THESE SCANNERS PICK UP ALL KINDS OF STUFF. GOOD STUFF, BAD STUFF. THE TROUBLE IS YOU CAN'T TELL WHAT'S WHAT. SO THERE' A NODULE ON THE LUNG. WELL, IT COULD BE CANCER, MAY NOT BE CANCER. NOW WE MAY NEED TO PUT A NEEDLE IN YOUR LUNG. THERE'S A VERY TELLING CASE REPORT FROM THE CHAIRMAN OF RADIOLOGY AT EMORY WHO UNDERWENT SOMETHING CALLED A VIRTUAL COLONNOGRAPHY TO AVOID COLONOSCOPY, GET A CT SCANNER. OKAY. THEY DISCOVERED SOMETHING IN HIS LIVER. ALL RIGHT. YOU KNOW, HE HAS A BIOPSY, AND THAT'S NOTHING. DON'T WORRY ABOUT IT. BUT DURING THAT BIOPSY, THEY SEE THAT THERE'S A LITTLE LUNG NODULE. SO THEY SAY, LOOK, YOU KNOW, I DON'T KNOW WHAT TO SAY BUT IT COULD BE CANCER. YOU SHOULD HAVE IT OUT. AND SHOWS -- BUT WE HAVE THIS WAY OF STICKING A LITTLE SCOPE IN THERE AND TAKING IT OUT, NO BIG DEAL. OKAY, LET'S DO THAT. DOES THAT. IT'S BENIGN. BUT HE HAS RIB PAIN FOR THE NEXT SIX MONTHS IN A PREVENTS HIM FROM WORKING. AND SO IF YOU PLAY BACK THE STORY, HE ACTUALLY WAS A HEALTHY GUY THAT UNDERWENT PROCEDURES FOR NO REASON. THERE'S A REAL DANGER TO SCREENING THE GENERAL POPULATION WITH THESE IMAGING TECHNIQUES. THAT'S THE LESSON. >> ANYTHING ELSE? >> ALL RIGHT. THANK YOU VERY MUCH. [END OF PROGRAM]