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Squamous Cell Carcinoma Tonsil Icd 9

Demystifying Medicine 2014 Human Papillomavirus Preventing Cancer

SO THE STORY WITH PAPILLOMA VIRUS IS MANY THEMES THAT INTERSECT WITH IT. SO THESE ARE JUST SOME OF THE QUESTIONS THAT WENT THROUGH MY MIND AND I HOPE AS YOU HEAR THE PRESENTATIONS TODAY, YOU’LL CERTAINLY FEEL FREE AND ENCOURAGED TO SPEAK UP AT ANY TIME, AND THEN ASK YOUR QUESTIONS. SO ONE OF THE THINGS THAT I WONDERED IS 50 OF WOMEN ACQUIRE PAPILLOMAVIRUS INFECTION WITHIN A FEW YEARS OF FIRST INTERCOURSE, WHY IS THE CANCER INCIDENCE MUCH LESS WHAT’S THE DIFFERENCE AND WHAT’S RESPONSIBLE FOR THE LARGE GROUP DIFFERENCES IN THE.

INCIDENCE OF CARCINOMA ASSOCIATED WITH THE PAPILLOMAVIRUS HOW IS PAPILLOMAVIRUS ASSOCIATED WITH HEAD AND NECK CANCERS HOW EFFECTIVE IS THE VACCINE HOW SAFE IS IT HOW LONG IS IT EFFECTIVE WHY DON’T WE VACCINATE MALES AND WHY DO THEY RECOMMEND VACCINATING GIRLS AT AGE 12 DOES VACCINATION REDUCE THE FREQUENCY WITH WHICH WOMEN GET PAP SMEARS SEXUAL MA BEHAVIOR IS THERE ANY EVIDENCE THAT IF A YOUNG WOMAN IS VACCINATED INAUDIBLE ONE OWHAT ARE THE NATIONAL AND EVEN INTERNATIONAL CHALLENGES AND AS ALWAYS IS IN MEDICINE, WHAT’S NEXT SO WE’RE VERY FORTUNATE TO HAVE.

TWO SPEAKERS TODAY WHO DEAL WITH ON ONE HAND PARTICULARLY THE CLINICAL AND TO SOME EXTENT THE CELL BIOLOGICAL MECHANISM OF HEAD AND NECK CANCER, THAT’S CARTER VAN WAES, HE RECEIVED HIS DEGREE AT THE UNIVERSITY OF CHICAGO, AND HERE AT THE NIH IS THE DIRECTOR OF THE SURGERY BRANCH OF WHAT I REFER TO AS THE DENTAL INSTITUTE BECAUSE I CAN’T REMEMBER ALL CRANIOPHARYNGEAL RIGHT. THANK YOU. OUR SECOND SPEAKER IS DOUGLAS LOWY, WHO TRAINED AT STANFORD, CAME HERE TO THE NIH, HAS BEEN INTERESTED THROUGHOUT HIS CAREER.

IN ONCOGENIC VIRUSES. IT’S THROUGH THE WORK THAT HE AND JOHN SCHILLER AND THE CANCER INSTITUTE THAT GAVE RISE TO THE DEVELOPMENT OF THE VACCINE AGAINST HUMAN PAPILLOMAVIRUS, THAT FORM CLOSELY RELATED CANCER IN MEN AND WOMEN, BUT PARTICULARLY IN WOMEN. SO WE’RE VERY GRATEFUL FOR YOU AND IN ADDITION, DR. VAN WAES HAS ASKED ONE OF HIS PATIENTS TO COME, WHO HAS BEEN HERE ONCE BEFORE. AND WAS KIND ENOUGH TO SPEND HIS TIME AND TELL YOU HIS STORY. SO CARTER, WOULD YOU PLEASE THANK YOU VERY MUCH. PLEASURE TO BE HERE TODAY AND TO.

SHARE THE PODIUM WITH SPEAK A LITTLE BIT TODAY ABOUT AN EMERGING PROBLEM THAT’S RELATED TO HUMAN PAPILLOMAVIRUS. JENNINGS CANTRELL IS GOING TO JOIN US TO TELL US ABOUT HIS EXPERIENCE WITH HEAD AND NECK CANCER. I’M ON. CAN PEOPLE HEAR ME IN THE BACK OKAY. CAN YOU HEAR ME NOW ARE YOU ABLE TO TURN UP THE MICROPHONE HOW IS THAT SO AS I WAS SAYING, MY PATIENT, JENNINGS CANTRELL, HAS BEEN KIND ENOUGH TO JOIN US TODAY, AND THEN DOUG LOWY IS GOING TO TALK ABOUT PREVENTION OF HPV RELATED.

CANCERS. SO THE SLIDES ARE NOT ADVANCING. THERE WE GO. SO TODAY I’M GOING TO SPEAK ABOUT AND JUST GIVE AN OVERVIEW ABOUT HUMAN PAPILLOMAVIRUS AND CANCER IN THE UNITED STATES. DOUG IS GOING TO TALK ABOUT IT AS A MUCH WIDER PROBLEM AS WELL, AND ALSO SPEAK ABOUT HPV AND OVEREAT LOGIC FACTORS FOR HEAD AND NECK CANCER, BECAUSE THERE MAY BE SOME EXCLUSIVE ROLE OF HPV AND OTHER FACTORS IN CERTAIN SUBSETS OF THESE CANCERS, BUT THERE ALSO MAY BE SOME OVERLAP IN THE SUSCEPTIBILITY TO THESE HEAD AND NECK CANCERS.

AND MR. CANTRELL WILL DISCUSS HIS CASE WITH US. I’LL BRIEFLY TALK ABOUT HIS NIH PROTOCOL TREATMENT, ALTHOUGH THAT’S NOT REALLY THE FOCUS OF THE TOPIC TODAY, AND THEN DOUG WILL SPEAK ABOUT VACCINES. SO DOUG WAS KIND ENOUGH TO PROVIDE A SLIDE THAT SUMMARIZES THE PROBLEM IN THE UNITED STATES. IN THE PAST, HPV WAS IMPLICATED INITIALLY IN CERVICAL CARCINOMA IN WOMEN, AND THIS IS NOW NOT THE ONLY PROBLEM IN THE UNITED STATES. THERE’S BEEN AN INCREASE IN THE INCIDENCE OF A NUMBER OF OTHER SITES THAT HAVE BEEN IMPLICATED.

IN HPV RELATED MALIGNANCIES INCLUDING THE VULVA, VAGINA, PENIS, AND MORE RECENTLY IT’S BECOME CLEAR IN THE LAST DECADE OR SO THAT THE OROPHARYNX, WHICH IS THE PART OF THE HEAD AND NECK AT THE BACK OF THE MOUTH, WHERE THE TONSILS LIE RIGHT BEFORE THE PHARYNX, IS ALSO A SITE FOR INFECTION AND DEVELOPMENT OF CANCERS THAT ARE RELATED TO THIS DISEASE. IN THE U.S., IT’S EMERGED TO BE IMPLICATED IN ABOUT 70 TO 80 OF OR OWOROPHARYNGEAL CANCERS, AND THIS HAS INCREASED OVER THE PERIOD OF 1988 TO 2004 APPROXIMATELY THREE.

FOLD. THIS SLIDE JUST HIGHLIGHTS SOME OF THE MEASURES OF THAT USING SAMPLES FROM TUMORS THAT WERE TAKEN DURING FOURYEAR WINDOWS FROM OVER THAT INTERVAL, SHOWING AN INCREASE IN THE USING A STANDARD ASSAY FOR HPV, USING HPV 16 VIRAL LOAD, THE E6, E7 MARKER, WHICH IS ONE OF THE VIRAL O ONG ONCOGENES, YOU CAN SEE THAT OVER THIS PERIOD, THERE’S BEEN AN INCREASE UP TO THE RANGE OF ABOUT 70 OF O OROPHARYNGEAL SQUAMOUS E CELL CARCINOMAS. ALSO IN THIS PUBLICATION, IT SHOWS THAT THERE’S ALSO BEEN A.

TREND IN DEVELOPING COUNTRIES, PARTICULARLY IN THE TOP PANEL, PANEL A, OROPHARYNGEAL CANCERS ARE SHOWN IN YELLOW, THEN ORAL CAVITY AND LUNG CANCERS ARE SHOWN IN BLUE AND GRAY, AND THOSE HAVE BEEN ASSOCIATED PRIMARILY WITH THE TOBACCORELATED SUBSET OF THESE TYPES OF HEAD AND NECK CANCERS. AND YOU CAN SEE IN THE DEVELOPING COUNTRIES, PANEL A, FOR EXAMPLE, THAT THE TREND OF THE GRAY BARS FOR LUNG CANCER HAS BEEN DECLINING, WHEREAS THE TREND IN THE YELLOW BARS IS MOVING TO THE RIGHT, INDICATING AN INCREASE IN PREVALENCE. THIS INCLUDES THE UNITED STATES,.

BUT ALSO A NUMBER OF OTHER DEVELOPING COUNTRIES. AND THIS IS MORE CLEAR IN MEN BECAUSE OF THE DIVERGENCE IN HABITS RELATED TO TOBACCO USE WITH A DECLINE IN MEN AND THE INCREASE IN HPV IN MEN AND ON THE OTHER HAND, WOMEN, SINCE THE RISE OF TOBACCO USE HAS SOMEWHAT TRAILED THAT OF MEN IN THE 20TH CENTURY, THAT INCREASE IS STILL UNDERWAY FOR LUNG CANCER AND ORAL CAVITY CANCER, BUT ALSO THERE’S AN INCREASE IN THE HPVRELATED OROPHARYNX CASES. THE OTHER ETIOLOGIC FACTORS THAT ARE INVOLVED IN DEVELOPMENT OF.

HEAD AND NECK CANCER IS TOBACCO USE, IS THE OTHER MAJOR ETIOLOGIC AGENT, AND IN CONTRAST TO MOST HEAD AND NECK CANCERS WHERE 70 ARE CAUSED BY TOBACCO AND ABOUT 30 OR 25 OR 30 ARE RELATED TO HPV OVERALL, AT THE SITE OF THE OROPHARYNX, IT’S THE OTHER WAY AROUND. MOST OF THESE 70 TO 80 ARE RELATED TO HPV, AND 25 ARE TOBACCORELATED WITHOUT EVIDENCE FOR HPV AND ANOTHER 5 MAY INVOLVE OTHER FACTORS INCLUDING HEREDITARY SUSCEPTIBLE, CHEMICAL EXPOSURE AND RADIATION, AND ALTHOUGH WE SEPARATE THESE THIS WAY FOR THE PURPOSE OF DEFINING.

THOSE WHICH ARE HPVPOSITIVE AND HPVNEGATIVE, IN FACT MANY PATIENTS THROUGH OUR HPV POSITIVE ARE ALSO TOBACCO USERS AT SOME POINT IN THEIR LIFE OR HAVE OTHER TYPES OF EXPOSURES, SO IT’S QUITE POSSIBLE THAT THE DEVELOP. THESE CANCERS WHICH DOESN’T OCCUR TO EVERYONE WITH HPV MAY ALSO BE ASSOCIATED WITH ADDITIONAL ALTERATIONS THAT OCCUR AS A RESULT OF THEIR PERSONAL EXPOSURES. SO WHERE DOES OROPHARYNGEAL SQUAMOUS CELL CARCINOMA ARISE I MENTIONED THAT IT’S ASSOCIATED WITH THE AREA OF THE TONSILS, AND MOST TIMES WHEN WE THINK OF THE TONSILS, WE THINK ABOUT.

THOSE TWO LARGE THINGS ON EITHER SIDE OF THE BACK OF OUR MOUTH THAT WE SEE IN THE MIRROR, BUT THERE ARE ALSO PARTS OF THAT THAT YOU CAN’T SEE, AND THOSE ARE AT THE BASE OF THE TONGUE. THOSE ARE CALLED THE LINGUAL TONSILS, AND THIS IS THE AREA THAT OUR PATIENT WAS AFFECTED BY, AND ALSO THERE IS TONSILLAR TISSUE UP IN THE AREA OF THE ADENOID, IN THE NASOPHARYNX, AND IT’S INTERESTING THAT THESE ARE THE SITES IN THE HEAD AND NECK CANCER IN WHICH THERE IS A VIRAL.

ETIOLOGY IN THE ADENOID AREA, EPSTEINBARR VIRUS HAS BEEN INVOLVED IN NASOPHARYNGEAL THOSE THAT ARE IN THE BASE OF THE TONGUE, THE LINGUAL TONSILS, ARE ASSOCIATED PRIMARILY WITH HPVRELATED CANCERS. HOWEVER, THERE HAS BEEN SOME RECENT REPORTS THAT HPV IS ALSO IMPLICATED IN CERTAIN NASOPHARYNGEAL CANCERS, PARTICULARLY IN NORTH AMERICA, SO THIS IS ALSO A SITE THAT MAY BE IMPORTANT TO THIS. THE REASON FOR THIS MAY HAVE TO DO WITH THE STRUCTURE OF THE TONSILS TO SOME DEGREE, THEY HAVE A VERY THIN EPITHELIUM AND THIS EPITHELIUM OVERLIES A.

COMPARTMENT WHICH IS OUR IMMUNE DEFENSES IN THAT AREA, MAY HAVE SOME TYPE OF INTERACTION THAT PRECIPITATES OR ENHANCES THE EFFECTIVITY OF THE VIRUS AND ITS ABILITY TO ESTABLISH ITSELF AND PERHAPS CANCER. SO WE’LL NOW SIT DOWN FOR A FEW MINUTES TO MEET WITH MR. CANTRELL ABOUT HIS CASE, AND I HAVE SOME OF IT SUMMARIZED UP ON THE SLIDE WHICH WE MAY BOTH TURN TO BECAUSE OUR MEMORY MAY NOT SERVE US COMPLETELY IN PRESENTING HIS CASE, BUT I’LL MOVE OVER HERE WITH HIM AND WE’LL SIT DOWN AND TALK A LITTLE.

BIT ABOUT HIS CASE PRESENTATION. I’M GOING TO TURN THIS THIS WAY. GOOD AFTERNOON. THIS WAS IN NOVEMBER OF 2008, I THINK WHEN YOU CAME TO SEE US. MAYBE YOU COULD TELL EVERYONE A LITTLE BIT ABOUT HOW LONG BEFORE THAT YOU OR YOUR WIFE NOTICED WHAT WAS GOING ON AND WHAT YOU THOUGHT AT THE TIME. gtgt WELL, IN THE SUMMER OF 2008, I DEVELOPED A SORE THROAT, WHICH IS UNLIKE ANY SORE THROAT THAT I HAD EVER HAD BEFORE. AND IT WAS VERY STRANGE. BUT I JUST DIDN’T MAKE THE.

CONNECTION TO ANY KIND OF SERIOUS ILLNESS. MY WIFE TELLS ME SINCE THEN THAT ABOUT EIGHT TO NINE MONTHS BEFORE THAT, SHE HAD NOTICED MY BREATH CHANGED, THE SMELL OF MY BREATH CHANGED. IT DEVELOPED SORT OF A MUSTY SMELL, LIKE THE SMELL OF OLD BOOKS. BUT SHE DIDN’T SHE THOUGHT IT WAS ODD BUT SHE DIDN’T MAKE A CONNECTION TO ANY KIND OF SERIOUS ILLNESS EITHER. SO I’M IN THE CATASTROPHE BUSINESS AND I FOUND MYSELF WORKING IN NEBRASKA, IN OCTOBER OF 2008, AND WHILE I WAS THERE, A NODE SPRANG OUT UNDERNEATH MY.

JAW, RIGHT ABOUT HERE, AND I WENT TO A SORT OF WHAT YOU MIGHT THINK OF AS A DOC IN A BOX, YOU KNOW, A LITTLE PRACTITIONER THAT WORKED OUT OF A LITTLE OFFICE, AND HE GAVE ME AN ANTIBIOTIC AND HE SAID, IF THIS DOESN’T GO AWAY IN 10 DAYS, YOU SHOULD SEE AN ENT. AND SO WITHOUT GIVING YOU TOO MUCH OF THE PLAYBYPLAY OF HOW THAT HAPPENED, WITHIN THE 10 DAYS, IT DIDN’T GO AWAY, I DID SEE AN ENT, HE TOLD ME I SHOULD IMMEDIATELY GET A CT SCAN, OR IT.

WAS AN MRI, I CAN’T REMEMBER WHICH ONE IT WAS, AND I DID HAVE THAT TEST. THAT SAME AFTERNOON, ACTUALLY. AND HE CALLED ME THE NEXT DAY AT WORK AND SAID THAT I HAD A MASS, AND THAT HE WANTED TO SEE ME. I WENT IN TO HIS OFFICE AND HE SAID THAT I HAD A MASS WHICH INDICATED A CANCER SOMEWHERE IN THE NEIGHBORHOOD OF STAGE 2 TO 3, HE DIDN’T KNOW FOR SURE WHAT, AND HE SAID HE DIDN’T KNOW EXACTLY WHAT IT WAS, BUT HE SAID IT WAS ABOUT AN 80 CHANCE THAT.

IT WAS SQUAMOUS CELL CANCER. SO I WAS ON A PLANE THE NEXT DAY FOR HOME, AND THE DAY AFTER I ARRIVED, WE’RE TALKING AGAIN LATE OCTOBER STILL, BECAUSE THESE EVENTS WERE HAPPENING, I PUSHED THEM ALONG AS RAPIDLY AS I COULD, AND I SAW A HEAD, NECK ENT HERE IN FIR FAIRFAX, AND SHE TOOK I HAD THE DISK THAT WAS THE IMAGE OF THE TEST THAT HAD BEEN DONE, AND SHE TOOK A LOOK AT IT AND SHE EXAMINED ME AND SHE SAID, WHAT I’M SEEING SHE.

USED A SCOPE, AND DON’T KNOW THE NAME OF IT, BUT I’M SURE THESE FOLKS KNOW WHAT I’M TALKING ABOUT. AND SHE SAID, I DON’T SEE ON THE SCOPE WHAT I SEE ON THE DISK, AND I DON’T UNDERSTAND WHAT THAT IS. AND SHE COULDN’T SEE ANYTHING ON THE SURFACE OF MY TONGUE. AND SO SHE SCHEDULED A BIOPSY AND SHE PERFORMED THE BIPS. TURNS OUBIOPSY. TURNS OUT THE CANCER WAS IN MY TONGUE, COULD NOT BE SEEN WITH THE AID OF A SCOPE. APPARENTLY SHE NEVER ACTUALLY SPOKE TO ME ABOUT IT, SHE TOLD.

MY WIFE, THAT I WAS A STAGE IV. AND SHE LEFT IT TO MY WIFE TO TELL ME. AND SHE HAD SOME CONNECTION HERE, I BELIEVE WITH DR. VAN WAES, AND SO I CONTACTED THEM AND IT TURNS OUT THAT THEY HAD A STUDY THAT INVOLVED TREATMENT HERE, AND I CAME IN AND SAW HIM AND THEY DECIDED TO ACCEPT ME IN THE PROGRAM, AND THEY BEGAN A PROGRAM OF RADIOLOGY AND CHEMOTHERAPY, WHICH BEGAN, I BELIEVE, ON DECEMBER 1 OF 2008. AND I WAS TREATED THROUGH JANUARY 26TH, 2009 WITH.

CHEMOTHERAPY AND RADIATION, AND IT WAS AN IMRT MACHINE THAT THEY REFERRED TO AS A TOMO MACHINE, WHICH IS APPARENTLY MORE TISSUESPARING THAN STANDARD IMRT MACHINE. LATER THAT YEAR, THEY FOUND A METASTASIS IN MY LEFT LUNG, A NODE, AND IT WAS REMOVED HERE AT NIH IN LATE SEPTEMBER OF 2009, AND I’VE HAD A NUMBER OF PET SCANS SINCE THEN, AND BIOPSIES OF ONE THING OR ANOTHER. IT LOOKS AS THOUGH THAT I AM CANCERFREE, AND I HAVE QUITE A NUMBER OF RESIDUAL PROBLEMS CAUSED BY THE TREATMENT, BUT IN.

VIEW OF THE FACT THAT I AM STILL HERE, I FEEL THAT IT’S PROBABLY A GOOD IDEA TO VIEW THOSE AS IN A SOMEWHAT FIL PHILOSOPHIC WAY. gtgt THANKS. APPLAUSE gtgt IN TERMS OF WHAT YOU THINK MAY HAVE BEEN SOME OF THE THINGS YOU WERE EXPOSED TO OR MAY HAVE CAUSED THIS, WHAT ARE SOME OF THE THINGS YOU HAD TOLD US AT THE TIME THAT YOU REMEMBER gtgt WELL, I SERVED IN VIETNAM AND WAS EXPOSED TO AGENT ORANGE. THERE WERE I OCCASIONALLY SMOKED A PIPE OR CIGAR, AND WHEN.

I SAY OCCASIONALLY, I MEAN IT WAS NOT UNCOMMON FOR ME TO GO SIX MONTHS WITHOUT SMOKING A PIPE OR A CIGAR, SO OCCASIONALLY IN MY CASE MEANS VERY OCCASIONALLY. I NEVER SMOKED CIGARETTES OF EVER IN MY LIFE. AND SO THOSE, AND NORMAL LIVING, OR WHAT I WOULD GUESS BE POSSIBLE AGENTS OF CAUSATION. gtgt SO YOU HAD ALSO HAD AN HPV TEST DONE ON THE TUMOR SPECIMEN WHEN YOU HAD THE OUTSIDE EVALUATION gtgt YES. THE ENT THAT I SAW HERE, WHEN I GOT BACK TO FAIRFAX, DID AS PART.

OF HER EXAMINATION OF ME A TEST FOR HPV AND IT WAS NEGATIVE. AND SO WHEN SHE TOLD MY WIFE ABOUT THE STAGE IV, SHE SAID WELL, OF COURSE IF HE WERE IF HE HAD BEEN POSITIVE WITH THE HPV, HE WOULD HAVE A HIGHER LIKELIHOOD OF BEING CURED, OR ACHIEVING A STATUS OF NO FURTHER CANCER. BECAUSE, OF COURSE, USING THE WORD CURED IS A SERIOUS NONO APPARENTLY. BUT SHE SAID HE’S NEGATIVE FOR HPV. SO WE CAN’T COUNT ON THAT. gtgt OKAY. SO I THINK WITH THAT, I’LL GO.

AHEAD AND GO BACK UP AND TELL THE REST OF THE THE STORY AND A LITTLE BIT ABOUT OH, SURE, SURE. gtgt DOES ANYONE HAVE ANY QUESTIONS YES, SIR. INAUDIBLE gtgt APPARENTLY. gtgt INAUDIBLE gtgt I NEVER HAD ANYONE SAY THAT. IT IS TRUE THAT WHEN I WAS YOUNGER, MY WIFE USED TO COMPLAIN THAT MY SNORING RATTLED THE WINDOWS, LITERALLY. BUT IN LATER YEARS, LAST 25, 30 YEARS, THAT PROBLEM DIMINISHED AND WENT AWAY, SO NO ONE HAS SUGGESTED THAT THAT WAS A CAUSE. gtgt SO THAT’S WHERE WE LEFT.

THINGS. BY THE OUTSIDE SCAN AND THE BIOPSY, IT APPEARED TO BE A STAGE THE PRIMARY SIZE OF THIS TUMOR WAS WHAT WE CALL A T2 ON A SCALE OF 4, AND HAVING A NECK NODE AND ALSO ON SCAN HAVING MORE THAN ONE NODE, ONE ON ONE SIDE AND ONE ON THE OTHER, IT WAS CALLED AN N2C. THERE WE GO. SO AT THAT TIME, THERE WAS ALSO NO EVIDENCE THAT THIS HAD SPREAD ANYWHERE ELSE BEYOND THE HEAD AND THE NECK REGION. SO WHEN HE WAS SCANNED HERE, A.

MONTH LATER, PRETTY MUCH THE SAME STORY, ALTHOUGH THERE WERE MULTIPLE LYMPH NODES IN THE NECK AND THIS TUMOR WAS ACTUALLY FAIRLY LARGE, IT EXTENDED ACROSS THE BACK OF THE TONGUE FROM ONE SIDE ACROSS THE MIDLINE. IN TERMS OF IMPLICATIONS FOR THERAPY, THE BACK OF THE TONGUE IS A FAIRLY UNFOR GIVING AREA FOR SURGICAL TREATMENT, WHEN IT GOES ACROSS MORE THAN HALF OF THE TONGUE AND REALLY REQUIRES REMOVAL OF THE WHOLE TONGUE. AND LEAVES PEOPLE BASICALLY CRIPPLED IN TERMS OF THEIR SPEECH. SO OVER THE LAST 20 YEARS OR SO,.

THE TREATMENT OF COMBINING CHEMOTHERAPY OR DRUG TREATMENT WITH RADIATION HAS EVOLVED AND HAS BEEN SHOWN TO BE FAIRLY ACTIVE IN THIS AREA, IN PART WE’RE LEARNING NOW PERHAPS BECAUSE THESE ARE HPVRELATED CANCERS. AND SO HE UNDERWENT TREATMENT WITH AN INVESTIGATIONAL REGIMEN WHICH COMBINED TWO DRUGS, ONE CALLED BORTESIMIB AND SER TUCKS MIB, I’LL GIVE A LITTLE BACKGROUND FOR THE RATIONALE OF THAT, CETUXIMAB IS AN ANTIBODY THERAPY FIRST DEVELOPED FROM AN ANTIBODY THAT WAS FOUND IN THE 1980s TO BLOCK THE EPIDERMAL GROWTH FACTOR RECEPTOR, WHICH IS SEEN IN THE UPPER RIGHTHAND.

CORNER THERE ON THE CELL SURFACE, AND IT’S AN IMPORTANT GROWTH SIGNAL FOR HEAD AND NECK AND OTHER EPITHELIAL CANCERS AND IT SIGNALS INTO THE CELL THROUGH A NUMBER OF PATHWAY, INCLUDING MITOGEN ACTIVATED PROTEASE IN THESE CANCERS, THE ROLE OF INFLAMMATION I MENTIONED TO YOU EARLIER THAT THESE CANCERS HAVE, THEY DEVELOP IN LYMPHOID TYPE TISSUE IN THE BASE OF THE TONGUE AND THE TONSILS AND ALSO APPEAR TO HAVE FAIRLY STRONG SIGNALS OF A NUMBER OF DIFFERENT CYTOKINES THAT ALSO SIGNAL TO ACTIVATE DOWNSTREAM PATHWAYS INCLUDING THE NF KA PA B PATHWAY.

SO THE TWO DRUGS USED IN THE STUDY WERE DESIGNED TO TARGET WITH AND ITS ACTIVATION AND EGF AND ITS DOWNSTREAM PATHWAYS USING CETUXIMAB. AND RADIATION TO ACTIVATE THE P53 FAMILY, WHICH IS INVOLVED IN INDUCING CELL DEATH AND IS ALSO INHIBITORY FOR GROWTH. AND THERE’S JUST A NUMBER OF THE TARGET GENES WITH THE OBJECT TV OF THESE DRUGS, WAS TO INHIBIT THE PHENOTYPE OR THE CANCER CELL, ITS PROLIFERATION, SURVIVAL OF THE CELLS AND THE BLOOD VESSEL FORMATION AND INFLAMMATION. SO THE STUDY DESIGN WAS OH TO GIVE THE CETUXIMAB DRUG WEEKLY.

AND TO GIVE THE VOR TEASE MIB TWICE WEEKLY, FOR THREE WEEKS, WITH WITH TIME OFF IN BETWEEN OF ONE WEEK, AND THIS WAS COMBINED DURING THE TIME WITH RADIATION THERAPY. THIS WAS REPORTED AS THE STUDY WAS REPORTED IN CLINICAL CANCER RESEARCH IN 2011. SO THE OUTCOME IN MR. CANTRELL’S CASE IS THAT HE HAD CT SCANS THREE MONTHS AFTER TREATMENT THAT SHOWED A COMPLETE RESPONSE OR ELIMINATION OF THIS MASS IN THE BASE OF HIS TONGUE WHICH WE COULD ALSO SEE BOTH IN THE CLINIC AND IN THE OPERATING ROOM.

AND ENDOSCOPICALLY IN THE BIOPSY OF THAT AREA DIDN’T SHOW ANY SIGN OF CANCER LEFT AT THAT SITE SITE. SO HE WAS CONSIDERED A COMPLETE RESPONSE AT THAT POINT, BUT ONLY A FEW MONTHS LATER, HE HAD A NEW LUNG NODULE WHICH HAD NOT BEEN SEEN UP TO THAT TIME, AND THIS WAS RESECTED BY OUR THORACIC SURGEONS HERE, A SINGLE NODULE, AND THIS SHOWED A POORLY DIFFERENTIATED SQUAMOUS CELL CARCINOMA THAT WAS VERY SIMILAR TO THE ONE IN THE BACK OF HIS TONGUE, AND WHAT WAS INTERESTING ABOUT THIS WAS WE ASKED THEM TO.

STAIN IT FOR A MARKER, WHICH IS A MARKER THAT IS USUALLY INCREASED IN HPV POSITIVE CANCERS AND THIS CAME UP POSITIVE FOR P16, WHICH IS A MARKER THAT’S CONSISTENT WITH AN HPV POSITIVE PRIMARY TONGUE TUMOR. AND MR. CANTRELL IS NOW APPROACHING FIVE YEARS OF DISEASEFREE SURVIVAL FROM THE TIME OF HIS LAST TREATMENT. WHAT WE’VE LEARNED ABOUT PHARYNGEAL SQUAMOUS CELL CARCINOMA IS THAT IT IS A DIFFERENT DISEASE THAN THE TO TOBACCORELATED CANCERS WHICH HAVE A MUCH WORSE PROGRES PROGNOSIS OF THE ONE OF THE DIFFERENCES ALSO HIGHLIGHTED IN THE SAME ARTICLE.

WE WERE TALKING ABOUT EARLIER AND WE’RE PICKING BACK UP ON AGAIN IS THAT THE MEDIAN SURVIVAL IS MUCH CLOSER TO FIVE YEARS FOR HALF THE PATIENTS SURVIVING FIVE YEARS OR LONGER COMPARED WITH TWO YEARS FOR THE TOBACCO RELATED MALIGNANCIES, AND AGAIN THIS IMPROVEMENT IN SURVIVAL IN OR OW OROPHARYNGEAL CANCER HAS TRENDED OVER THE YEARS TO OCCUR IN PATIENTS IN THE SAME INTERVAL IN WHICH WE’VE SEEN THIS INCREASE IN POSITIVITY IN OROPHARYNGEAL CARCINOMAS IN PLACE OF TOBACCORELATED OROPHARYNGEAL CARCINOMAS. SO I’M GOING TO END MY TALK JUST BY TALKING A LITTLE ABOUT SOME.

OF THE EMERGING DATA THAT WE’RE GETTING FROM THE NEW CANCER GENOME AT LAS INITIATIVE IN WHICH ALMOST 300 HEAD AND NECK CANCERS HAVE NOW BEEN SEQUENCED USING THE NEXT GENERATION SEQUENCING TECHNOLOGY THAT’S ALLOWED US TO MAKE A ROAD MAB OR A CIRCUIT DIAGRAM OF THE TYPES OF ALTERATIONS IN THESE DIFFERENT CANCERS AND FOR HUMAN PAPILLOMAVIRUS SUBSET OF THESE CANCERS, WHAT WE KNOW IS THAT THE VIRUS SERVES AS ONE OF THE KEY ON COPROTEINS INACTIVATE A COUPLE OF THE TUMOR SUPPRESSOR GENES POSH IN THIS TYPE OF IMPORTANT IN TH IS TYPE OF.

CANCER, AND IN ADDITION TO THAT, AS A RESULT OF THAT, THESE CANCERS HAVE A DIFFERENT GENETIC ALTERATIONS THAN THE TOBACCORELATED MALIGNANCIES, WHICH IN MOST CASES RESULT IN INACTIVATION OF AN UPSTREAM CYCLIN DEPENDENT KINASE WHICH IS THE GENE THAT ENCODES P16. SO THAT’S PATIENTS WHO HAVE HPVRELATED CANCERS TEND TO HAVE IP16 IN MOST CASED, AND AS WELL THESE CANCERS SHOW MUCH FEWER GENETIC ALTERATIONS THAN TOBACCORELATED PLAGU MALIGNANCIES WHICH HAVE GENETIC ALTERATIONS IN MOST OF THESE OTHER MOLECULES THAT IN HPV, THERE APPEAR TO BE IN THESE CANCERS A MUCH MORE.

FOCUSED ALTERATION IN THE PI3 KINASE CATALYTIC STUB UNIT, WHICH IS AFFECTED IN ABOUT 60 OF THESE CANCERS, AND ALSO THE P63, ANOTHER P53 FAMILY MEMBER, THIS GENE IS AMPLIFIED ALONG WITH PI3 KINASE IN ABOUT 30 OF THESE CANCERS AND ADDITIONAL MUTATIONS AND ANOTHER 30 IN THE CATALYTIC SUBUNIT. SO ACROSS THESE PATHWAYS, PATHWAYS INVOLVED IN CELL GROWTH, CELL SURVIVAL AND DEATH, IMMUNITY, AND IN DIFFERENTIATION APPEAR TO BE AFFECTED BY GENETIC ALTERATIONS. ONE OF THE ONES THAT’S PARTICULARLY NOTEWORTHY IN THE HPV POSITIVE CANCERS IS A LOSS OF A GENE CALLED TRAF3, EITHER A.

LOSS OR MUTATION, AND THIS OCCURS IN ABOUT ONEFIFTH OF THE HPVRELATED CANCERS, BUT NOT IN THE TOBACCO RELATED PLAGUE NANCYS. THIS IS OFF PARTICULAR INTEREST BECAUSE TRAF3 IS NOT ONLY A NEGATIVE RE REGULATOR FOR ONE OF THE TRANSCRIPTION FACTORS THAT ACTIVATES MANY GENES INVOLVED IN PROLIFERATION, CELL SURVIVAL INFLAMMATION GENESIS BUT IT’S ALSO A PROTEIN THAT’S INVOLVED IN INTRODUCING INTERFERON RESPONSE FACTORS AND INTERFERONS WHICH ARE INVOLVED IN THE IMMUNITY TO THE N.A. VIRUSES, SO WE THINK THIS MAY BE ONE OF THE IMPORTANT EVENTS THAT DIFFERENTIATES HPVPOSITIVE.

CANCERS FROM TOBACCORELATED CANCERS. WE’VE KNOWN FOR MANY YEARS THAT CISPLATIN IS AN ACTIVE AGENT IN HEAD AND NECK CANCER AND PARTICULARLY IN HPVRELATED OROPHARYNGEAL CARCINOMAS IN COMBINATION WITH RADIATION, AND THESE TWO STANDARD THERAPIES APPEAR TO HAVE SOME OF THEIR EFFECTS IN DNA DAMAGING EFFECTS ON CELL PROLIFERATION, ALSO APPEAR TO CAUSE THE DEGRADATION OF ONE OF THOSE ON COPROTEINS P63 AND ALSO BECAUSE THESE HPVRELATED CANCERS MAY HAVE SOME RESIDUAL P53, IT MAY BE THAT RADIATION IS EFFECTIVE THROUGH THE OF THE VIRAL ONCOPROTEIN’S INCOMPLETE INHIBITION OF P53 IN THESE.

TUMORS. IN ADDITION WITH OUR KNOWLEDGE ABOUT PI3 KINASE, IT MAY BE POSSIBLE TO TARGET THESE WITH INHIBITORS AND PERHAPS REDUCE THE NEED FOR SOME OF THE MORE TOXIC AGENTS WHICH WE USE CURRENTLY IN THOSE TYPES OF CANCERS.S. SO IN SUMMARY, INCIDENCE IS INCREASING IN THE U.S. AND WORLDWIDE. THESE CANCERS ARE ASSOCIATED WITH IMPROVED SURVIVAL. THEY HAVE FEWER ALTERATIONS THAN HPV NEGATIVE SQUAMOUS CELL CARCINOMAS, ONE OF THE MARKERS FOR THIS WE CAN USE CLINICALLY IS THE RETENTION OF P16, AND BECAUSE THEY HAVE DECREASED BUT NOT MUTANT P53 IN CONTRAST TO.

THE TOBACCORELATED MALIGNANCIES, THEY MAY HAVE A MAY ONE OF THE GREATER FACTORS RESPONSIVENESS TO OUR STANDARD THERAPIES, BUT WE’RE LEARNING ABOUT THE ALTERATION SPECIFICALLY AFFECTING THESE CANCERS IN THE CELL CYCLE, AND THE TRAF INTERFERON PATHWAYS MAY DEFINE SOME NEW POTENTIAL TARGETS FOR PREVENTION AS WELL AS THERAPY. ANY QUESTIONS RELATED TO THAT gtgt THANK YOU VERY MUCH. APPLAUSE THE SAME PATHWAYS INVOLVED IN HPVRELATED TUMORS IN THE CERVIX AND OTHER ORGANS gtgt JUST IN TERMS OF THE OVERALL GENOMIC ALTERATIONS BETWEEN THE TWO CANCERS, PARTICULARLY THE HPV SUBSET OF HEAD AND NECK.

IT DOESN’T APPEAR THAT TRAF3 LOSS IS AS COMMON IN CERVICAL CANCER, FROM WHAT WE KNOW. gtgt SO THE THERAPIES THAT ARE SOMEWHAT SI SIMILAR ALL RIGHT. WELL, THANK YOU. gtgt GOOD AFTERNOON, EVERYONE. IT’S REALLY A PLEASURE AND AN HONOR TO HAVE BEEN INVITED AND ALSO TO BE ABLE TO PARTICIPATE WITH DR. VAN WAES AND WITH MR. CANTRELL. YOU’VE REALLY HEARD, I THINK, A VERY GOOD INTRODUCTION AS WELL AS A STRIKING EXAMPLE OF HOW IMPROVED TREATMENT CAN ACTUALLY HELP PATIENTS, AND IN ADDITION, CAN ALSO IMPROVE QUALITY OF.

LIFE. MR. CANTRELL DIDN’T DISCLOSE TO US EXACTLY WHAT HIS SIDE EFFECTS WERE, BUT I THINK IT WAS INSTRUCTIVE THAT THE EXTENSIVENESS OF HIS CANCER LED ACTUALLY TO A DECISION TO DO CHEMOTHERAPY PLUS RADIATION RATHER THAN SURGERY IN ORDER TO TRY TO PRESERVE HIS ABILITY TO SPEAK, ET CETERA. I AM GOING TO CONTINUE AND TO SWITCH GEARS A BIT TO REALLY TRY TO TALK MORE IN THE PREVENTION A AREA THAN IN THE THERAPEUTIC AREA, BUT ALSO TO TRY TO ADDRESS SOME ALTHOUGH PERHAPS NOT ALL OF THE QUESTIONS THAT WAS ASKING.

AT THE BEGINNING. FIRST A LITTLE BIT OF HOUSEKEEPING DISCLOSURES. I HAVE BEEN INVOLVED IN THE DEVELOPMENT OF THE LICENSED VACCINES AND OUR TECHNOLOGY HAS BEEN LICENSED TO THE TWO COMPANIES THAT MAKE THE VACCINES AND I WILL DISCUSS POTENTIAL OFFLABEL USE OF THE TWO FDAAPPROVED VACCINES. WHAT I’M GOING TO TALK ABOUT IS GO BACK BRIEFLY OVER THE NOTION OF HPV INFECTION AND DE, AND THEN TALK ABOUT PREVENTION BOTH BY SCREENING AND VACCINATION, AND THEN AFTER WE TALK ABOUT THAT A BIT, TO MOVE TO HPVBASED SCREENING AND TO FEWER THAN.

THREE VACCINE DOSES, WHICH IS WHAT THE VACCINES HAVE BEEN APPROVED FOR UP TO NOW, AND THEN END WITH A LITTLE BIT ABOUT SECOND GENERATION VACCINES. AS WE MENTIONED, I’VE WORKED VERY CLOSELY WITH JOHN SCHILLER NOW FOR CLOSE TO 30 YEARS, AND WE’VE HAD WONDERFUL COLLABORATORS BOTH WITHIN THE LABORATORY, WITHIN THE NIH EXTRAMURALLY, AND IMPORTANTLY, INTERNATIONALLY. THE IMPLICATIONS OF HPV AS HAVE REALLY BEEN PROFOUND AND EVEN HARVEY ALTAR WOULD APPROVE, I THINK, R. WITH THE IDENTIFICATION HPV 16 AND 18 IN THE 1980s, LED FINALLY TO HIS RECEIVING A NOBEL.

PRIZE 25 YEARS AFTER THE DISCOVERY OF THESE TWO VIRUSES. AND AS WITH ANY OTHER INFECTIOUS AGENT THAT IS THE CAUSE OF AN IMPORTANT DISEASE, I HOACH THAT YOU HOPE T HAT THE DISCOVERY OF THE AGENT WILL LEAD TO TARGETS AT INTERVENTIONS AGAINST THE AGENT BECAUSE IN PRINCIPLE, THAT MIGHT BE EASIER THAN TRYING TO DEVELOP TREATMENT THAT IS SPECIFICALLY TARGETED TO THE DISEASE. AND I MUST CONFESS THAT WHAT DR. VAN WAES WAS TALKING ABOUT FOR MR. CANTRELL IS REALLY TRYING TO TARGET THE DISEASE AS OPPOSED TO TARGETING THE HPV IN.

THE DISEASE. IN THIS SITUATION, OF COURSE, SINCE THERE WASN’T AN OBVIOUS PRESENCE OF HPV, THE OPTION DIDN’T SEEM TO BE THERE ANYWAY, AND WE DON’T HAVE ANY APPROVED TREATMENT AGAINST HPV ENCODED PROTEINS, FOR EXAMPLE, FOR THESE CANCERS. BUT THIS IDENTIFICATION LED TO AN EXPLOSION IN UNDERSTANDING THE NATURAL HISTORY OF HPV INFECTION, THE PATHOGENESIS OF CERVICAL CANCER AND ULTIMATELY TO THE PATHOGENESIS OF OTHER CANCERS, BUT THE IDENTIFICATION OF OTHER HPVASSOCIATED CANCERS IS A DIRECT OUTCOME OF THE IDENTIFICATION OF THE VIRUS. FOR EXAMPLE, WE DIDN’T REALLY UNDERSTAND THAT HPV MIGHT BE AN.

IMPORTANT CAUSE OF OROPHARYNX CANCER PRY TO TH PRIOR TO THE DISCOVERY OF HPV. SO FIRST IN TERMS OF DISEASE UNDERSTANDING, IT’S VERY IMPORTANT. THE SPECTRUM OF DISEASE I’M GOING TO CONTRAST WHAT I’M SHOWING YOU HERE ON THIS SLIDE WITH THE NEXT SLIDE, WHICH DR. VAN WAES HPV AFFECTS A HIGH PERCENTAGE OF PEOPLE WHO ARE SEXUALLY ACTIVE IT, BUT IN THE DEVELOPING WORLD, IT MAINLY CAUSES CERVICAL CANCER, AND I’LL EXPLAIN WHY IN A LITTLE BIT. THIS PROFILE SHOWS YOU THE NUMBER OF CASES OF CERVICAL CANCER THAT OCCUR IN THE.

DEVELOPING WORLD ABOUT A HALF MILLION CASES PER YEAR, AND THE OTHER HPVASSOCIATED CANCERS ARE MUCH LESS COMMON IN THE DEVELOPING WORLD. TO PUT THIS IN PERSPECTIVE, MORE THAN 90 OF HPVASSOCIATED CANCER IS CERVICAL CANCER, AND GLOBALLY, ABOUT 85 OF THOSE CANCERS OCCUR IN THE DEVELOPING WORLD, AND ABOUT 88 OF THE DEATHS, SO THAT FROM A GLOBAL PERSPECTIVE, CERVICAL CANCER IS THE NUMBER ONE PROBLEM, AND IT IS A PARTICULAR PROBLEM IN THE DEVELOPING WORLD AND IN MANY COUNTRIES IN THE DEVELOPING WORLD, CERVICAL CANCER IS THE MOST COMMON CANCER OF WOMEN, AND.

IT’S A PARTICULAR PROBLEM BECAUSE IT TENDS TO STRIKE WOMEN WHO STILL ARE RAISING CHILDREN, ET CETERA, RATHER THAN OCCURRING IN WOMEN WHO ARE GRANDPARENTS, ET CETERA. IF YOU CONTRAST THAT PROFILE WITH WHAT IS SEEN IN THE UNITED STATES, YOU CAN APPRECIATE THAT THE OTHER CANCERS, THE NONCERVICAL CANCERS, ARE APPROXIMATELY AS NUMEROUS AS THE CERVICAL AS THE CERVICAL CANCERS. THESE WHITE AREAS ARE THE CANCERS OF THESE TYPES THAT ARE NOT HPVASSOCIATED. ANOTHER IMPORTANT DIFFERENCE IS THAT WHILE IN THE DEVELOPING WORLD, APPROXIMATELY 95 OF HPVASSOCIATED CANCERS OCCUR IN.

WOMEN IN THE UNITED STATES, IT’S MORE LIKE 70 OR SO OCCUR IN WOMEN, SO THAT ON THE ORDER OF THREE OUT OF 10 HPVASSOCIATED CANCERS IN THE UNITED STATES ARE OCCURRING IN MEN. SO THIS IS ANOTHER CLEAR DIFFERENCE, AND OROPHARYNX CANCER, AS DR. VAN WAES HAS MENTIONED, INCIDENCE HAS INCREASED SUBSTANTIALLY OVER THE LAST 25 YEARS, AND IT IS PREDOMINANTLY MALES WHO DEVELOP THIS DISEASE, ABOUT A 31 RATIO OF MALES TO FEMALES DEVELOPING THIS DISEASE. THUS FAR, CERVICAL CANCER STILL OCCURS ONLY IN WOMEN, EVEN IN THE UNITED STATES.

I’M SORRY, THAT WAS A JOKE. SO WHEN ASKED AT THE BEGINNING IF HPV INFECTION IS SO COMMON IN WOMEN, WHY IS CERVICAL CANCER RELATIVELY UNCOMMON, AND FIRST I WOULD POINT OUT THAT OUR ESTIMATES NOW ARE THAT PROBABLY 75 TO 80 OF WOMEN WILL HAVE AT LEAST ONE GENITAL HPV INFECTION DURING THEIR LIFETIME. SO IT’S A VERY COMMON IT’S A VERY COMMON INFECTION, AND IT’S ALMOST ALWAYS GOING TO BE A SEXUALLY TRANSMITTED INFECTION. LUCKILY, THE VAST MAJORITY OF BOTH MEN AND WOMEN WHO ARE INFECTED BY HPV, THE INFECTION.

IS LIMITED, WHICH MEANS AFTER A PERIOD OF BETWEEN SIX MONTHS AND TWO YEARS, THE INFECTION GOES AWAY SPONTANEOU SPONTANEOUSLY. HOWEVER, THERE IS A SUBSET OF INDIVIDUALS IN WHOM INSTEAD OF GOING AWAY, THE INFECTION PERSISTS, AND PERSISTENT INFECTION IS A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF HPVASSOCIATED CANCER, WHETHER IT IS CERVICAL CANCER, OROPHARYNX CANCER OR ANY OF THE OTHER CANCERS. AND WHAT THIS SHOWS HERE IS THAT YOU CAN HAVE SPONTANEOUS REGRESSION, AND SUBCLINICAL INSPECTION IS MUCH MORE EXON IN THE U.SCOMMONIN THE U.S. THAN CANCER. PART OF THE DECREASE HERE IS.

BECAUSE WE HAVE EFFECTIVE SCREENING, PAP SMEAR SCREENING WAS DEVELOPED APRO APPROXIMATELY 60 YEARS AGO AND HAS HAD A BIG IMPACT IN REDUCING THE INCIDENCE AND MORTALITY FROM CERVICAL CANCER, AND I HAVE A SLIDE FOR THAT LATER. BUT THERE ARE STILL ABOUT 12,000 CASES PER YEAR IN THE UNITED STATES. ANOTHER ADVANCE THAT IS ATTRIBUTABLE TO THE DISCOVERY OF HPV AS A CAUSATIVE AGENT OF CERVICAL CANCER AND THEN OF THESE OTHER CANCERS, IS THE DEVELOPMENT OF HPVBASED CERVICAL SCREENING AND HPV INTERVENTIONS OF THE PREVENTIVE VACCINE, AND THEORETICALLY, DEVELOPMENT OF THERAPEUTIC.

VACCINES OR ANTIVIRALS, BUT THERE HAS BEEN LESS ACTIVITY IN THESE AREAS. I WOULD POINT OUT THAT IN ADDITION TO HEPATITIS B VIRUS, WHERE THERE IS PREVENTIVE VACCINATION, AND WITH HPV, HEPATITIS C VIRUS IS ALSO AN IMPORTANT CAUSE OF LIVER CANCER AND BECOMING PROGRESSIVELY MORE IMPORTANT IN THE UNITED STATES. THERE HAVE RECENTLY BEEN MAJOR ADVANCES IN THE EFFECTIVENESS OF THE ANTIVIRAL TREATMENT OF HCV INFECTION, AND SO WE HOPE THAT THE INCIDENCE OF SERIOUS SIRROSIS, LIVER FAILURE AND LIVER CANCER, ATTRIBUTABLE TO HCV INFECTION WILL GO DOWN OVER TIME AS MORE PEOPLE ARE ABLE TO.

BE TREATED. WITH HCV INFECTION, THE PROTECTIVE IMMUNE RESPONSES ARE NOT WELL UNDERSTOOD SO IT HAS TURNED OUT TO BE EASIER TO DEVELOP APT VIRALS AGAINST HCV INFECTION THAN TO DEVELOP A PRIMARY PREVENTIVE VACCINE. I JUST WANT TO POINT OUT THE WAY HPVBASED SCREENING IS DONE IN THE UNITED STATES IS IN CONJUNCTION WITH CYTOLOGY, AND IT’S USED AS A A PRIMARY SCREENING TEST IN SOME KUN TRIES. TWO WEEKS AGO, THE FDA ADVISORY COMMITTEE SAID THAT THE TESTS CAN BE USED FOR PRIMARY SCREENING, DIFFERENT FDAAPPROVED TESTS, SO I THINK.

THAT PRIMARY HPVBASED SCREENING IS COMING TO THE U.S. AND WILL PROBABLY BE AVAILABLE QUITE SHORTLY. I’LL EXPLAIN TO YOU PART OF THE REASON. THIS LOOKS AT THE INCIDENCE OF CERVICAL CANCER OVER THE LAST 40 YEARS. AND WHAT I HOPE YOU CAN APPRECIATE IS THAT THERE’S BOTH SQUAMOUS CELL CANCER AND ADENOCARCINOMA. THE DECREASED INCIDENCE IS REALLY PRIMARILY ATTRIBUTABLE TO THE DECREASE IN SQUAMOUS CELL CARCINOMA, LESS SO WITH ADENOCARCINOMA, CYTOLOGY IS A MUCH BETTER SCREENING TEST FOR SQUAMOUS CELL CANCER THAN FOR ADENOCARCINOMA. AND THE ADVENT OF HPVBASED SCREENING CAN IMPROVE THE.

RECOGNITION OR THE DETECTION OF THE INCIPIENT LEAGUES THAT MAY GO AND PROGRESS TO ADENOCARCINOMA, AND SO WE ARE HOPING THAT THE USE OF HPV TESTING NOT ONLY WILL BE ABLE TO CONTINUE THIS DOWNWARD CYCLE HERE FOR SQUAMOUS CELL CARCINOMA, BUT ALSO TO HAVE AN IMPACT ON THE INCIDENCE AND ULTIMATELY THE MORTALITY FROM ADENOCARCINOMA. IT’S REALLY IMPORTANT TO UNDERSTAND THAT ALTHOUGH THE HEPATITIS B VIRUS VACCINE WAS FIRST INTRODUCED IN THE 1980s, THE EVIDENCE FOR REDUCTION OF LIVER CANCER IS QUITE LIMITED UP TO THIS TIME BECAUSE THERE’S SUCH A LONG INTERVAL BETWEEN THE.

TIME OF THE INFECTION AND THE DEVELOPMENT OF THE CANCER THAT YOU ARE TRYING TO PREVENT. AND THE SITUATION IS VERY SIMILAR WITH HPV TO THE EXTENT THAT YOU’RE TRYING TO PREVENT CANCER. HPV INFECTION ALSO LEADS TO SOME NONMALIGNANT INFECTION, FOR EXAMPLE, GENITAL WARTS, AND THERE, THE IMPACT CAN BE SEEN MUCH FASTER. BUT WE HAVE TWO MODALITIES OF TRYING TO PREVENT CANCER. ONE IS SCREENING AND THE OTHER IS VACCINATION, AND I HAVE THIS SLIDE HERE TO TRY TO IMPRESS ON YOU THAT ACTUALLY THERE ARE SOME THEORETICAL ADVANTAGES OF.

SCREENING COMPARED TO VACCINATION. AND THAT IS, IN PRINCIPLE, YOU CAN HAVE AN IMPACT ON REDUCING INCIDENCE OF MORTALITY ATTRIBUTABLE TO CANCER MUCH FASTER IF YOU DO SCREENING THAN IF YOU DO VACCINATION. BECAUSE VACCINATION IS PREVENTING THE INITIAL INFECTION. WHEREAS SCREENING, YOU ALREADY HAVE THE INITIAL INFECTION, IT’S GONE ON FOR SOME PERIOD OF TIME, AND YOU THEN ARE IDENTIFYING THE PRECANCERS, AND THIS THEN LEADS TO THE REDUCTION IN CANCER. SO WHILE VACCINATION MAY BE AS EFFICIENT AS SCREENING, IT TAKES LONGER TO SEE THE IMPACT IF THE END POINT THAT YOU’RE LOOKING.

FOR IS A REDUCTION OF CANCER OR A REDUCTION IN MORTALITY ATTRIBUTABLE TO CANCER. NOURISH AND THIS SHOWS YOU THE RESULT OF A RANDOMIZED CONTROL TRIAL OF SCREENING THAT WAS CARRIED OUT IN RURAL INDIA AND RECORDED ABOUT FOUR YEARS AGO, IT WAS SPONSORED BY THE INTERNATIONAL AGENCY FOR RESEARCH ON KEAN SER CANCER, WHICH IS AN ARM OF THE WORLD HEALTH ORGANIZATION. AND WHAT I WOULD HOPE YOU WILL SEE HERE IS THAT THIS IS LOOKING AT THE MORTALITY RATE OF THE WOMEN WHO WERE IN THE TRIAL, WOMEN OF AGE BETWEEN 30 AND 59,.

THEY WERE SCREENED ONCE. AND THEN FOLLOWED UP BASED ON THE RESULTS OF THE SCREEN. THESE ARE THE WOMEN WHO RECEIVE HPVBASED TESTING. THE OTHER WOMEN IN THE OTHER GROUPS WERE EITHER ESSENTIALLY STANDARD CONTROL GROUP, CYTOLOGY, OR WHAT’S CALLED VISUAL INSPECTION WITH ACETIC ACID, WHICH VERY RECENTLY HAS BEEN SHOWN TO HAVE SOME IMPACT. BUT FOR CYTOLOGY AND TO HAVE IMPACT, YOU NEED TO DO SEVERAL ROUNDS OF SCREENING, WHICH LOGISTICALLY IS OFTEN VERY DIFFICULT IN RESOURCEPOOR AREAS. HPVBASED SCREENING, HOWEVER, IS SUFFICIENT LISTENSTIVE THAT IT WAS ABLE TO HAVE AN IMPACT ON.

MORTALITY WITHIN LESS THAN 10 YEARS. SO I JUST WANT TO MAKE SURE THAT WE ALL UNDERSTAND THAT SCREENING HAS REAL POTENTIAL UTILITY. I NOW WANT TO TURN TO THE ISSUE OF PRIMARY HPV VACCINATION. AND THE LICENSED VACCINES AGAINST MICROBIAL AGENTS ARE MAINLY PREVENTIVE, AND THE INDUCTION OF WHAT ARE CALLED NEUTRALIZING ANTIBODIES TENDS TO BE CRITICAL. NEUTRALIZING ANTIBODIES ARE THE ANTIBODIES THAT INTERFERE WITH THE ABILITY OF THE AGENT TO BE INFECTIOUS FOR THE HOST. HPVS CONTAIN VIRAL ONCO GENES, YOU ALREADY HEARD ABOUT E6 AND E7, E5 IS ANOTHER ONE, AND SINCE.

PREVENTIVE VACCINES ARE GIVEN TO NORMAL POPULATIONS, THE NOTION WAS THAT YOU PROBABLY WOULD NOT WANT TO BE GIVING ONCOGENES TO NORMAL POPULATION, AND SO A SUBUNIT VACCINE LACKING THESE ONCOGENES PROBABLY MADE MORE SENSE IF IT COULD BE SUCCESSFUL, AND PAPILLOMAVIRUSES ENCODE TWO PROTEINS THAT INDUCE NEUTRALIZING ANTIBODIES, WHICH ARE THE TWO CAPSID PROTEINS, THE CAPSID IS THE VIRUS PARTICLE, AND IS COMPOSED OF TWO PROTEINS, L1 AND L2. L1 CONTAINS WHAT ARE CALLED THE IMMUNODOMINANT NEUTRALIZATION EPITOPES. WHAT THIS MEANS IS THAT IF YOU IMMUNIZE WITH THE WITH THE VIRUS.

PARTICLE, THE MAIN NEUTRALIZING ANTIBODIES ARE DIRECTED AGAINST L1, AND THEY ARE CONFORMATIONALLY DEPENDENT, WHICH MEANS THEY ASSUME SOME KIND OF NATIVE STRUCTURE RATHER THAN THEIR LINEAR EXTENDED STRUCTURE, AND THE KEY HYPOTHESIS WAS THAT L1 COULD SELFASSEMBLE TO MAKE EMPTY PARTICLES HAVING A CONFORMATION THAT INDUCES HIGH LEVELS OF NEUTRALIZING ANTIBODIES, AND THAT INDEED WAS THE CASE. THIS IS A PICTURE OF HPV 16 VIRUSLIKE PARTICLES MADE IN INSECT CELLS BY INFECTING THEM WITH A RECOMBINANT BACK LOW VIRUS THAT EXPRESSES L1. AND THEY ASSEMBLE SPONTANEOUSLY INTO THESE PARTICLES, AND THE.

PARTICLES HAVE WHAT SEEMS TO BE THE ARRANGEMENT AND CONFORMATION OF AUTHENTIC VIRUS PARTICLES EXCEPT THAT THEY ARE DEVOID OF THE VIRAL GENOME. AND THEY’RE ABLE TO INDUCE HIGH TITERS OF NEUTRALIZING ANTIBODY, THEY’RE NONINFECTIOUS AND NONONCOGENIC. THERE ARE TWO COMMERCIAL HPV VACCINES. ONE, GARDASIL MADE BY MERCK, AND THE OTHER, SERVE RIX, MADE BY GLAXOSMITHKLINE. THE GLAXOSMITHKLINE VACCINE IS A BIVALENT VACCINE, IT USES VIRUSLIKE PARTICLES FROM HPV 16 AND 18, AND TOGETHER, THEY ACCOUNT FOR ABOUT 70 OF CERVICAL CANCER AND EVEN HIGHER PERCENTAGE OF THE NONCERVICAL CANCERS. THE MERCK VACCINE, IN ADDITION.

TO HAVING PARTICLES FOR HPV 16 AND 18, ALSO HAVE PARTICLES FOR HPV 6 AND 11. AND TOGETHER, HPV 6 AND 11 ACCOUNT FOR ABOUT 90 OF GENITAL WARTS, AND I WANT YOU TO REMEMBER THAT, BECAUSE I’M GOING TO SHOW YOU A SLIDE ABOUT THE IMPACT IN AUSTRALIA ON THE INCIDENCE OF GENITAL WARTS IN THE LAST FEW YEARS SINCE THE INTRODUCTION OF THE VACCINE. I WOULD POINT OUT THAT BOTH VACCINES ARE GIVEN IN INTRAMUSCULAR INJECTIONS OVER SIX MONTHS. THE ADJUVANT THAT IS USED BY GLAXOSMITHKLINE IS A PROPRIETARY.

ADJUVANT CALLED ASO4, AND IT’S A LITTLE BIT MORE IMMUNOGENIC THAN THE ALUM ADJUVANT THAT IS USED IN THE MERCK VACCINE, AND I JUST WANT YOU TO BE AWARE THAT THERE ARE SOME DIFFERENCES. IN THE UNITED STATES, AND MOST PLACES IN THE WORLD, THE MERCK VACCINE DOMINATES IN TERMS OF MARKET SHARE. AND THE REASON FOR THAT IS THAT THE MERCK VACCINE WAS APPROVED IN 2006, WHEREAS THE GSK VACCINE WASN’T APPROVED UNTIL 2009. SONE OF THE OTHER QUESTIONS THAT WAS ASKING ABOUT IS WHAT ABOUT SAFETY, OKAY I HAVE ANOTHER SLIDE THAT.

DISCUSSES THIS FROM A SOCIOLOGICAL PERSPECTIVE, BUT THIS IS TO TRY OH TO DISCUSS THIS FROM A SCIENTIFIC AND EVIDENCEBASED PERSPECTIVE. THE CENTERS FOR DISEASE CONTROL HAS A PASSIVE REPORTING SYSTEM CALLED THE VACCINE FOR A FEW YEARS AFTER THE INTRODUCTION OF THE VACCINE, THERE WERE THOUSANDS OF REPORTS THAT CAME IN OF DIFFERENT KINDS OF SIDE EFFECTS, AND THERE WAS A HIGHLY PUBLICIZE PAPER THAT WAS PUBLISHED IN THE JOURNAL OF THE MEDICAL TH THE AMERICAN MEDICAL ASSOCIATION FOUR OR FIVE YEARS AGO THAT IDENTIFIED THESE VARIOUS POTENTIAL SIDE EFFECTS.

AS BEING VACCINEASSOCIATED. WHAT THE CDC AND THE FDA DO IS THAT THEY FOLLOW UP THE RESULT WITH WHAT IS KNOWN AS THE VSD, WHICH IS THE VACCINE SAFETY DATA , AND THIS IS A PROSPECTIVE STUDY FROM SEVERAL MANAGED CARE ORGANIZATIONS THAT LOOKS AT WHAT THE SIDE EFFECTS ARE ASSOCIATED WITH A NUMBER OF DOSES. THE PRINCIPLE DIFFERENCE BETWEEN THE VAIRS AND THE VSV IS THE SAIRS IS ANECDOTE, THERE IS NO DENOMINATOR. IT JUST GIVES YOU A CERTAIN NUMBER OF CASES. THE VSV IS EVIDENT BECAUSE IT HAS BOTH A NUMERATOR AND A.

DENOMINATOR. IT TELLS YOU THE FREQUENCY OF SIDE EFFECTS FOR A CERTAIN NUMBER OF DOSES, AND IT HAS COMPARATORS. THERE’S M NO VACCINE RELATED RISK TO PRESPECIFIED OUTCOMES IN THIS STUDY FROM 2011 THAT WAS RECENTLY UPDATED WITH 1.5 MILLION DOSES PRESENTED AT THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES LAST YEAR. THE RATE OF AN FLAX IS IS SIMILAR TO THAT OF OTHER VEAK VACCINES AND THE RATE OF FAINTING IS SIMILAR TO THAT OF OTHER ADOLESCENT VACCINES. HOW ABOUT EFFICACY IN BLACK IS THE EFFICACY FOR THE MERCK VACCINE OND IN ORANGE IS.

THE EFFICACY FOR THE GSK VACCINE. AND THIS IS IN THE GROUP OF YOUNG WOMEN WHO WERE 16 TO 23 AT THE TIME OF VACCINATION WHO DURING THE VACCINATION PERIOD WERE VIRUSNEGATIVE ANDOR ANTIBODY WERE AP ANTIBODY NEGATIVE. THIS IS THE GROUP THAT IS CLOSEST TO THE TARGET GROUP THAT YOU WANT TO VACCINATE, BECAUSE YOU WANT TO VACCINATE PEOPLE WHO ARE NOT YET SEXUALLY ACTIVE, BUT IN ORDER TO DO THE TRIAL, THE TRIAL WAS CONDUCTED IN WOMEN WHO HAD HAD A LIMITED NUMBER OF SEXUAL PARTNERS BUT WERE.

SEXUALLY ACTIVE. AND WHEN LOOKING AT THIS SUBGROUP OF WOMEN, THE VACCINE EFFICACY IS OVER 90 AND IS CLOSE TO 100. FOR THE MERCK VACCINE, THERE ARE NUMEROUS END POINT, CLINICAL POINTS THAT WERE USED, MODERATE AND HIGH GRADE CERVICAL INTRAEPITHELIAL NEOPLASIA, WHICH IS PRECANCER, ESSENTIALLY, PRECANCER FOR VULVAR AND VAGINAL NEOPLASIA AND FOR THE MERCK VACCINE, ALSO GENITAL WARTS. AND THE MERCK VACCINE IS APPROVED BY THE FDA FOR ALL OF THESE INDICATIONS. THE GSK VACCINE WAS ANALYZED FOR A MORE LIMITED NUMBER OF OUTCOMES JUST FOR CERVICAL PRECANCER AND AGAIN HAD A.

PERFORMANCE THAT WAS VERY SIMILAR TO THAT OF THE MERCK VACCINE, BUT IT IS ONLY APPROVED FOR PREVENTION OF CERVICAL CANCER, NOT FOR THE OTHERS. HOWEVER, PART OF MY NOT OFF LABEL USE BUT AT LEAST MENTIONING, THERE’S EVERY REASON TO BELIEVE THAT THE GSK VACCINE WOULD BE JUST AS EFFICACIOUS IN PREVENTING INFECTION AND DISEASE AT THE OTHER SITES. HOWEVER, YOU WOULD NOT EXPECT IT TO BE AS EFFICACIOUS AGAINST GENITAL WARTS, AND WITH DATA THE DATA ACTUALLY SUPPORT THAT BUT I’M NOT GOING TO PRESENT THAT BECAUSE THE GSK VACCINE DOESN’T.

REALLY DOESN’T TARGET HPV 6 AND 11. SO WHAT ARE THE GOALS OF VACCINATION MOST PEOPLE THINK ABOUT THE GOALS OF VACCINATION BEING PRIMARILY TO REDUCE THE RISK OF INFECTION AND DISEASE IN VACCINEES. AND WHILE THAT IS CRITICALLY IMPORTANT, IN MY OPINION, ESPECIALLY WHEN IT COMES TO HPV VACCINATION, THAT’S JUST ONE OF THE GOALS. I THINK THAT THERE IS ALSO A SECOND GOAL, AND THAT IS TO INDIRECTLY REDUCE THE RISK OF INFECTION BY REDUCING THE PREVALENCE OF THE HPV VACCINE TYPES IN THE GENERAL POPULATION, WHICH IS KNOWN AS HERD IMMUNITY.

ONE OF THE FEATURES OF THE HPV VACCINE IS THAT NEITHER VACCINE IS APPROVED FOR PREVENTION OF OR OROPHARYNX CANCER. THE PRINCIPAL REASON FOR THAT IS THAT IN CONTRAST TO THE PRECANCERS THAT OCCUR IN THE ANAL CANAL, VULVAR OR VAGINAL, AND AT THE CERVIX, THERE IS NOT A WELLRECOGNIZED PRESERVE CAL PRECANCEROUS LEAGUES IN THE OROPHARYNX. AND THEREFORE, YOU DON’T HAVE THAT DISEASE TO FOLLOW TO SEE IF YOU ACTUALLY PREVENT IT. SO THE BEST THAT WE CAN DO IS TO SHOW THAT YOU CAN REDUCE THE RISK OF HPV INFECTION IN THE.

MOUTH, AND THE RELATIONSHIP BETWEEN HPV INFECTION IN THE MOUTH AND THE DEVELOPMENT OF OROPHARYNX CANCER IS MORE TENUOUS THAN THE RELATIONSHIP BETWEEN THE PRECANCERS IN THE GENITAL TRACT AND THE DEVELOPMENT OF CANCER. AND SO IT’S NOT APPROVED FOR THAT. BUT IN MY OPINION, THERE IS EVERY REASON TO EXPECT THAT IF YOU REDUCE THE PREVALENCE OF THE HPV, YOU WILL REDUCE EXPOSURE AND IT’S REALLY ALMOST IMPOSSIBLE TO IMAGINE THE SCENARIO. IF YOU REDUCE EXPOSURE, YOU WILL REDUCE THE INCIDENCE OF THIS DISEASE. SO I ACTUALLY THINK THAT BOTH OF.

THESE ARE IMPORTANT. NOW, HERE ARE TWO SLIDES OF GENITAL WARTS IN AUSTRALIA. IN AUSTRALIA, AS I’LL SHOW YOU IN A FEW SLIDES, WAS AN EARLY ADOPTER COUNTRY AND A RELATIVELY HIGH RATE OF HPV VACCINATION AMONG YOUNG WOMEN. IF YOU LOOK IN BLUE, THIS DOTTED LINE SHOWS YOU WHEN THE VACCINE WAS INITIATED IN 2007, AND THE INCIDENCE OF GENITAL WARTS AMONG YOUNG WOMEN WHO WERE LESS THAN 21 YEARS OF AGE WENT DOWN DRAMATICALLY IN THE ENSUING FOUR YEARS. IF YOU LOOK IN RED, THIS IS IN WOMEN 21 TO 30, MANY OF THESE.

WOMEN WERE VACCINATED. WOMEN OVER 30 WERE NOT VACCINATED, AND YOU CAN SEE THAT THE INCIDENCE OF GENITAL WARTS DID NOT GO DOWN IN THOSE UNVACCINATED WOMEN. EVEN MORE IMPRESSIVE ARE THE DATA IN THE MALES. BECAUSE DURING THIS TIME PERIOD, MALES WERE NOT VACCINATED. THEY RECENTLY HAD INITIATED VACCINATION OF MALES, BUT THESE DATA ARE COMPILED BEFORE MALE VACCINATION WAS INITIATED, AND THIS IS STRONG EVIDENCE OF HERD IMMUNITY. ONCE AGAIN, LOOKING IN BLUE, THESE ARE THE MEN WHO ARE UNDER 21, YOU CAN APPRECIATE THEIR INCIDENCE OF GENITAL WARTS WEPT.

DOWN DRAMATICALLY, ALTHOUGH NOT TO THE SAME DEGREE AS THE WOMEN, AND THE SAME THING IS TRUE FOR THE MEN WHO WERE 21 TO 30, AND 30 AND NO STATISTICALLY SIGNIFICANT CHANGE IN THE MEN WHO ARE OVER 30. SO I WANT TO SPEND A COUPLE OF MINUTES ASKING AND TRYING TO ADDRESS THE QUESTION, WHY IS THE VACCINE SO EFFECTIVE THERE WAS UNDERSTANDABLY GREAT SKEPTICISM ABOUT THE ABILITY OF SYSTEMIC IMMUNIZATION WITH A PROTEINBASED VACCINE TO BE ABLE TO REDUCE INFECTION AND DISEASE THAT IS CAUSED BY A LOCAL MUCOSAL INFECTION, BECAUSE THE.

PRINCIPAL TARGET WAS CERVICAL INFECTION, AND CERVICAL INFECTION IS A LOCAL MUCOSAL INFECTION. AND SO WE THINK THAT THERE ARE SORT OF THREE REASONS. THE FIRST IS THE REPETITIVE STRUCTURE OF THE VIRUSLIKE PARTICLE I MUTE JEAN IS IMMUNOGENIC. THIS IS SOMETHING THAT HAS BECOME MORE WIDELY RECOGNIZED IN THE RESEARCH COMMUNITY OVER THE LAST FEW YEARS, AND ACTUALLY IN JUNE, THERE’S GOING TO BE THE SECOND INTERNATIONAL CONFERENCE ON VIRUSLIKE PARTICLES AND NANOPARTICLE VACCINES BECAUSE OF THEIR IMMUNOJE NECESSITY IN A SMALL ADVERTISEMENT FOR MY PARTNER IN CRIME, JOHN SCHILLER,.

IS GOING TO BE GIVING THE KEYNOTE ADDRESS AT THAT MEETING. A SECOND REASON IS THAT THE TISSUE ASSOCIATED NEUTRALIZING ANTIBODIES ARE EXUDATED AT POTENTIAL SITES OF INFECTION. WHAT THAT MEANS IS THAT THE ANTIBODY LEVELS AT THESE SITES REFLECT THEIR LEVEL IN SERUM RATHER THAN THEIR LOWER LEVELS IN THE NONDISRUPTED GENITAL TRACT. AND I’LL SHOW YOU PICTURES ABOUT THAT IN THE NEXT TWO SLIDES. AND THEN FINALLY, HPV IS HIGHLY SUSCEPTIBLE TO NEUTRALIZING ANTIBODIES. SO THIS SLIDE SHOWS YOU THAT IN OUR MOUSE MODEL OF HPV INFECTION, THE FIRST STEP IN HPV.

INFECTION IS ACTUALLY BINDING TO THE BASEMENT MEMBRANE THAT SEPARATES THE EPITHELIUM FROM THE DERMIS. AND THIS IT REQUIRES TRAUMA, MICRO TRAUMA IN ORDER FOR THIS TO BE BINDING. HPV DOESN’T BIND TO THE APICAL SURFACE THAT IS THE UPPER SER FAST OF EPITHELIAL CELLS, EVEN THE COLUMNAR EPITHELIUM OF THE CERVICAL CANAL. BUT IT BINDS VERY AVIDLY TO THESE AREAS, AND IT INITIATES LIFE CYCLE WHILE STILL ON THE BASEMENT MEMBRANE, AND THEN ONLY LATER TRANSFERS TO THE TARGET EPITHELIAL CELL. NOW THIS CARTOON ESSENTIALLY SHOWS YOU WHAT HAPPENS IN AN.

IMMUNIZED INDIVIDUAL. THERE ARE LOW LEVELS OF ANTIBODIES IN THE CERVICAL CANAL, BUT HIGHER LEVELS REFLECTIVE OF WHAT’S IN THE SERUM THAT’S IN THE TISSUE. BUT AT THE POINT OF POTENTIAL INFECTION, THE BARRIER FUNCTION OF THE EPITHELIUM IS DISRUPTED SO YOU GET THE ANTIBODIES GOING INTO THIS AREA OF POTENTIAL INFECTION, SO WHEN THE VIRUS PARTICLE COMES IN, ANTIBODIES ACTUALLY RECOGNIZE THE PARTICLE, BIND TO IT AND INTERFERE WITH THE ABILITY OF THE VIRUS TO BIND TO THE BASEMENT MEMBRANE. AND EVEN AT LOW LEVELS, WE SEE BINDING TO THE BASEMENT MEMBRANE.

BUT YOU DON’T GET THE TRANSFER OF THE VIRUS TO THE TARGET EPITHELIAL CELL. SO THERE ARE TWO DIFFERENT MECHANISMS THERE. NOW I WANT TO SAY A FEW THINGS ABOUT, IF YOU WILL, UPTAKE OF THE HPV VACCINE, AND THERE ARE MAJOR DIFFERENCES DEPENDING ON THE COUNTRY WHERE YOU ARE. AND IN RED ARE SHOWN ONE DOSE AND IN BLUE ARE SHOWN THREE DOSES. IN THE UNITED KINGDOM, WHICH HAS SCHOOLBASED VACCINATIONS, YOU CAN APPRECIATE THAT PROBABLY 90 ARE FULLY VACCINATED. IN AUSTRALIA, THE NUMBER THAT ARE FULLY VA VACCINATED, IT’S A.

LITTLE BIT LOWER, BUT STILL A HIGH NUMBER. THE UNITED STATES, HOWEVER, WE ARE SUBSTANTIALLY LOWER SO YOU CAN EXPECT THAT THE IMPACT FROM THE VACCINE IS GOING TO BE LESS, AND JUST SO I DIDN’T WANT PEOPLE TO THINK THAT WE ARE LAST, THE UPTAKE IS EVEN LOWER. SO THE UPTAKE OF THE VACCINE IN THE UNITED STATES, THERE ARE SEVERAL REASONS, I’VE OUTLINED A FEW OF THEM HERE. ONE IS MEDICAL UNCERTAINTIES AT THE TIME OF FDA APPROVAL. SAFETY, DURATION OF PROTECTION, FOR EXAMPLE, WERE KEY ISSUES. THESE ISSUES HAVE LARGELY BEEN.

ADDRESSED POSITIVELY SUBSEQUENTLY TO THE EXTENT THAT THEY CAN BE. YOU KNOW, SINCE THE VACCINE HAS BEEN IN USE FOR REALLY ONLY SEVEN OR EIGHT YEARS, YOU DON’T HAVE DURATION OF EFFICACY MUCH BEYOND THAT, BUT THUS FAR IT SEEMS TO BE THE SAFETY DATA. PROVIDER HESITANCY IS SOMETHING THAT THE CENTERS FOR DISEASE CONTROL IDENTIFIED IS A MAJOR ISSUE, WHICH IS LACK OF STRONG VACCINE RECOMMENDATION FROM HEALTHCARE WORKERS IN THE UNITED STATES. THERE ALSO WAS PUSHBACK FROM EFFORTS TO MAKE THE VACCINE MANDATORY IN 2007, WHICH WAS THE.

YEAR AFTER IT WAS APPROVED AND FOR THOSE OF YOU WHO HAVE LONG ENOUGH MEMORIES BACK TO THE REPUBLICAN PRECEDENTIAL THE DATES, YOU KNOW, GOVERNOR PERRY GOT INTO SOME ISSUES WITH THE QUESTION OF TRYING TO MAKE THE VACCINE MANDATORY IN TEXAS. THEN THERE HAVE BEEN CONCERNS ABOUT VACCINATIONS PROMOTING SEXUAL DISINHIBITION, WHICH HAS ALSO HAD AN IMPACT. I JUST WANT TO SHOW YOU TWO SLIDES THAT SORT OF CONTRAST OR COMPARE WHAT THE STORY IS WITH CERVICAL CANCER INCIDENCE AND MORTALITY IN THE UNITED STATES BECAUSE IT REALLY IS QUITE.

REGIONAL, AND TO SEE WHAT HAPPENS WITH VACCINE IMPACT. THIS IS IN RED OUR HIGH INCIDENCE, OKAY THIS IS NOT THE REPUBLICAN STATES, OKAY AND THESE ARE NOT THE DEMOCRATIC STATES. BUT EVEN THE REPUBLICAN STATES THAT ARE LOCATED HERE WOULD PROBABLY RATHER BE BLUE, WHEN IT COMES TO CERVICAL CANCER IPS DENSINCIDENCE AND MORTALITY. SO I WANT TO YOU LOOK AT THE DISTRIBUTION HERE, AND HERE IS THE VACCINE UPTAKE AS OF 2011. HERE THE DARKER PURPLES ARE THE PLACES WITH MORE VACCINATION AND THE LIGHTER AREAS ARE PLACES WITH LESS.

AND IN GENERAL, THE AREAS THAT HAVE THE BIGGEST PROBLEM WITH CERVICAL CANCER ARE THE AREAS THAT THE VACCINE HAS BEEN UNDERUTILIZED. SO NOW, I WANT TO TALK A LITTLE BIT, WHAT’S BEING DONE THAT MIGHT CHANGE THIS OTHER THAN PEOPLE YELLING AND SCREAMING OR WHATEVER. SO THIS IS GOING TO BE LARGELY SCIENCEBASED, OKAY ONE THING IS, AS WYNN MENTIONED, WHAT ABOUT THE VECTORS WHAT ABOUT MALES SORRY. THAT WAS ME WHO SAID WHAT ABOUT THE VECTORS. AND SO MERCK DID SOME LESS INTENSIVE STUDIES OF MALES, AND SHOWED THAT THE VACCINE IS ALSO.

PROTECTIVE AGAINST MALES, BOTH AGAINST GENITAL WARTS AS WELL AS AGAINST ANAL DYSPLASIA, AND THE FDA GAVE APPROVAL FOR MALES BOTH FOR WARTS AND THE PREVENTION OF ANAL CANCER, AND THIS LED THE CDC ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES IN 2011 TO MAKE THE SAME RECOMMENDATION FOR BOYS AS FOR GIRLS. I JUST WANT TO POINT OUT THE MERCK VACCINE IS APPROVED FOR BOTH GENDERS, THE GSK VACCINE ONLY FOR GIRLS, ONCE AGAIN, OFF LABEL. THERE IS NO REASON TO BELIEVE THAT THE GSK VACCINE WOULD BE LESS EFFECTIVE IN MALES, BUT.

EFFICACY HAS NOT BEEN TESTED IN MALES. SO THAT’S ONE POTENTIAL WAY OF TRYING TO INCREASE THE UPTAKE. SECOND IS WOULD FEWER THAN THREE DOSES BE PROTECTIVE SO THESE DATA ARE TAKEN FROM THE NATIONAL CANCER INSTITUTE HAS BEEN CONDUCTING A TRIAL OF THE GSK VACCINE IN COT COSTA RICA, WHERE CERVICAL CANCER IS THE MOST COMMON CANCER IN WOMEN IN COSTA RICA. SOME OF THE WOMEN, INSTEAD OF THGETTING ALL THREE DOSE DOSES, OHM GOT ONE OR TWO DOSES. AND WE WERE ABLE TO THEN LOOK AT THE ATTACK RATE FOR THE WOMEN.

WHO GOT ONLY ONE OR TWO DOSE, AND BEFORE LOOKING AT THE VACCINATED GROUP, LOOK AT THE CONTROL GROUP. THE CONTROL GROUP WITH THREE DOSES, THE RATE OF ACD16 INFECTION PER HUNDRED WOMEN WAS APPROXIMATELY 8 HERE, 6 WITH TWO DOSES AND 8 WITH ONE DOSE, SO THERE DIDN’T SEEM TO BE ANY BEHAVIORAL DIFFERENCE, AND REMEMBER THIS IS A RANDOMIZED DOUBLE BLINDED TRIAL, SO NEITHER THE WOMEN NOR THE PEOPLE DOING THE EXAM KNOW WHO GOT WHICH WHETHER THEY WERE IN THE CONTROL GROUP OR IN THE VACCINATED GROUP THE HPV VACCINATED.

GROUP. YOU CAN APPRECIATE THE RATE OF PROTECTION, THE VACCINE EFFICACY FOR TWO IN ON AND ONE DOSES WERE AS GREAT AS VACCINE EFFICACY FOR THREE DOSES. AND I WOULD LIKE TO SAY THAT FOR TWO VACCINE DOSES, THE FUTURE IS NOW. THE FUTURE IS NOW OUTSIDE THE UNITED STATES. THE INITIAL REGULATORY APPROVAL FOR THREE DOSES IN GIRLS WAS CALLED ON THE BASIS OF WHAT’S CALLED NONINFERIORITY BRIDGING. WHAT THAT MEANS IS THAT THE YOUNGER ADOLESCENTS WERE APPROVED NOT BECAUSE OF EFFICACY, BUT BECAUSE THEIR IMMUNE RESPONSE TO THREE DOSES.

WAS NOT INFERIOR TO THE IMMUNE RESPONSE OF THE YOUNG WOMEN WHO WERE IN THE TRIALS WHERE THE GOOD EFFICACY WAS SHOWN. BUT THOSE STUDIES SHOWED THAT THE YOUNG ADOLESCENTS ACTUALLY MOUNTED A STRONGER IMMUNE RESPONSE THAN THE OLDER ADOLESCENTS WHO WERE IN THE CLINICAL TRIALS. AND SO THE MOTION OF COULD YOU GET AWAY WITH TWO DOSES INSTEAD OF THREE WAS ESSENTIALLY ADVANCED. AND TWO DOSES SEPARATED BY SIX MONTHS PRODUCE AN IMMUNE RESPONSE SIMILAR TO THOSE IN THE RESPONSES TO THREE DOSES IN THE EFFICACY TRIALS. AND THERE WAS A POSITIVE OPINION.

FROM THE EUROPEAN MEDICINES AGENCY, WHICH IS LIKE THE EUROPEAN FDA, COMMITTEE FOR MEDICAL PRODUCTS FOR HUMAN USE, FOR TWO DOSES FOR BOTH OF THE VACCINES. IN DECEMBER, THEY APPROVED THE GSK VACCINE FOR TWO DOSES IN YOUNG GIRLS 9 TO 14 YEARS OF AGE, AND LAST MONTH THE COMMITTEE RECOMMENDED THE MERCK VACCINE FOR TWO DOSES IN GIRLS AND BOYS 9 TO 13. THE EMA HAS NOT YET APPROVED IT, BUT APPROVAL IS ANTICIPATED. BUT I JUST WANT TO REPEAT THAT IN THE UNITED STATES, THE RECOMMENDATION IS FOR THREE.

DOSES. MY EXPECTATION IS THAT FIVE YEARS FROM NOW, WE’LL ALSO BE AT TWO DOSES, BUT WE’RE NOT THERE, BUT WE’RE NOT THERE NOW. THESE ARE THE IMMUNOGENICITY STUDIES OF THE COSTA RICA TRIAL WHOSE VACCINE EFFICACY RESULTS I SHOWED YOU A FEW MINUTES AGO. AND WHAT I WANT YOU TO SEE IS NOT JUST THE RESULTS FOR TWO AND THREE DOSES, IT’S QUITE SIMILAR BETWEEN TWO AND THREE DOSES, BUT WITH ONE DOSE, NOTE THAT THE ANTIBODY LEVELS DON’T GO DOWN OVER TIME. THIS IS A TOTALLY UNEXPECTED RESULT. PROTEIN BASED SUBUNIT VACCINES.

ALMOST ALWAYS, YOU NEED TO BE BOOSTED. THE CLASSIC IS THE TESS NA TETANUS TOX OID. SO THIS VACCINE IS ANALOGOUS IN THE SENSE THAT IT IS A PROTEINBASED VACCINE. WE THINK THAT THE STABLE ANTIBODY TITERS MAY BE ATTRIBUTABLE TO TWO FACTORS. ONE IS THAT THE PARTICLES ARE HIGHLY IMMUNOGENIC AS I MENTIONED, AND THE OTHER IS THAT THE GSK ADJUVANT INCLUDES WHAT’S CALLED A TLR4 AGONIST, WHICH ACTIVATES ANOTHER ACTIVATOR OF THE IMMUNE SYSTEM IN ADDITION TO ALUM. AND WE DON’T KNOW WHETHER THERE ARE IMPLICATIONS FOR OTHER VACCINES.

POSSIBLY THERE MIGHT BE A RANDOMIZED CONTROL TRIAL TO RIGOROUSLY TEST THE EFFICACY OF ONE DOSE. SINCE THIS IS CONTRARY TO EXPECTATION AND THIS WAS NOT A PRESPECIFIED PRIMARY OUTCOME OF THE TRIAL, YOU REALLY NEED TO DO A RIGOROUS RANDOMIZED CONTROL TRIAL BEFORE YOU WOULD ACCEPT THAT ONE DOSE WOULD BE USEFUL. I NOW WANT TO GET TO THE LAST TOPIC OF THE TALK, WHICH IS SECOND GENERATION VACCINES. I HAVE ABOUT FOUR SLIDES. THE GOAL WOULD BE EITHER TO MAKE PROTECTION LESS EXPENSIVE. ONE THING YOU COULD DO IS TO.

SIMPLY FIE VACCINE PRODUCTION OR ADMINISTRATION. THE MEASLES VACCINE, FOR EXAMPLE, IT’S AN RNA VIRUS, BUT THERE’S EXCESS CODING CAPACITY IN THE VACCINE, AND YOU CAN ACTUALLY ENCODE L1 FOR HPV 16, AND EXPRESS L1 IN MEASLES VACCINE AND AT LEAST IN MICE, IT INDUCES HIGH LEVELS OF NEUTRALIZING ANTIBODIES. AND YOU COULD JUST INCORPORATE THAT AND YOU COULD THEN GET YOUR FIRST DOSE, AT LEAST, WITH MEASLE VACCINE. CLOSER TO HOME IS THE BROADENING PROTECTIONS AGAINST MORE HPV TYPES, BECAUSE I’M GOING TO SHOW YOU SOME PRELIMINARY DATA FROM A.

NEW CANDIDATE OF VACCINES PRODUCED BY MERCK. IT COULD PREVENT HIGHER PROPORTION OF HPV INFECTION AND INCREASE BORDER PROTECTION, COULD REDUCE THE OF SCREENING AND YOU MIGHT BE ABLE TO LENGTHEN THE SCREENING INTERVAL, AND IT MIGHT LEAD TO INCREASED VACCINE UPTAKE. SO THIS DIE GRAMMATICALLY SHOWS YOU WHAT THE CURRENT VACCINES DO THAT THEY CAN PREVENT ABOUT 70 OF CERVICAL CANCER, AND WHAT MERCK HAS DONE IS TO ADD THE FIVE MOST COMMON ONCOGENIC HPV TYPES IN TERMS OF CAUSING CERVICAL CANCER, AND THIS CAN PREVENT IN PRINCIPLE CLOSE TO.

90 OF SERIOUS CERVICAL INFECTIONS. I’D POINT OUT THAT IT’S NOT ALL OF THEM, BUT IT’S THE VAST MAJORITY. AND THEY HAVE RECENTLY PRESENTED THEIR RESULTS IN ABSTRACT FORM AT A COUPLE OF RESEARCH CONFERENCE, AND SO THIS TELLS YOU THIS D503 ADDS THESE HPV TYPES, AND THEY DID A CLINICAL TRIAL THAT THE CONTROL GROUP ACTUALLY RECEIVED GARDASIL, THE QAW DRA VALENT VACCINE, AND THE PRIMARY END POINT WAS MODERATE CERVICAL INTRAEPITHELIAL NEOPLASIA, THAT’S MODERATE DYSPLASIA, AGAINST THE FIVE NEW HPV TYPES, AND IMMUNOLOGICAL NONINFERIORITY AGAINST THE OTHER FOUR TYPES, AND THE.

VACCINE EFFICACY AGAINST THE FIVE NEW TYPES WAS 96, AND THE PROTECTION AGAINST PERSISTENT INFECTION BY THOSE TYPES WAS ALSO 96. SO THIS WAS ONE CASE IN THE V503 GROUP VERSUS 27 CASES IN THE QAW DRA VALENT GROUP. YOU CAN LOOK ONLINE FOR IF YOU WANT MORE INFORMATION. IT HAS NOT YET BEEN PUBLIC. THIS IS TAKEN FROM A NATURAL HISTORY STUDY IN DENMARK, LOOKING AT WOMEN WHO HAVE HAD THEIR FIRST SCREENING TESTS FOR CERVICAL CANCER IN THEIR EARLY 20S. AND THEY’VE HAD ONE POSITIVE TEST OR IN THE CASE OF THIS.

ORANGE LINE, A NEGATIVE TEST, AND THEY’RE FOLLOWED UP THEN IN THE SYSTEM FOR THE NEXT 12 YEARS TO SEE WHAT HAPPENED. SO THESE ARE WOMEN WHO ARE HPV 16 POSITIVE, AND THEY ARE SITE LOGICALLY NORMAL. THEY HAVE A PAP SMEAR AT THIS TIME PERIOD, AND THEN THEY’RE FOLLOWED. WHAT I HOPE YOU CAN APPRECIATE IS THAT 1 IN 4 OF THEM DEVELOP HIGH GRADE DYSPLASIA OR INVASIVE CANCER OVER THE NEXT WELL YEARS. THERE’S AN INTERMEDIATE GROUP COMPOSED OF HPV 18, 31 AND 33, AND THERE OVER THE NEXT 12.

YEARS, IT’S ABOUT 15 OF THEM DEVELOP A HIGH GRADE DYSPLASIA OR WORSE. AND THEN IN BLUE ARE THE THERE’S A COCKTAIL OF 13 DIFFERENT HPV TYPES, WHICH IS ONE OF THE FDAAPPROVED TESTS, BUT IT’S BEEN FRACTION ATED SO THAT YOU EXCLUDE THESE FOUR TYPES, AND YOU CAN SEE THAT THE RATE OF DEVELOPMENT OF HIGH GRADE DYSPLASIA OVER THE NEXT 12 YEARS IS VERY LOW, AND YOU KNOW, A LITTLE BIT HIGHER THAN THAT OF THE WOMEN WHO ARE NEGATIVE. I’M SHOWING YOU THIS BECAUSE I THINK SINCE THESE FOUR TYPES ARE.

ALL IN THE NINEVALENT VACCINE, IF THEY WERE APPROVED BY THE FDA AND WERE WIDELY USED, IT WOULD IMPLY THAT THE FAST PROGRESSORS, THAT IS, THESE FOUR TYPES, COULD IN PRINCIPLE BE ELIMINATED FROM THE POPULATION, AND IT MIGHT BE SAFE TO START CERVICAL CANCER SCREENING AT A LATER AGE AS LONG AS THE WOMEN HAVE BEEN VACCINATED AND THE PREVALENCE OF THESE HPV TYPES WERE THERE. SO LET ME SUMMARIZE. HPV CAUSES SEVERAL DIFFERENT CANCERS, AS WELL AS GENITAL WARTS AND OTHER DISEASES. THE VACCINE CAN PREVENT THE BENIGN PREMALIGNANT AND.

MALIGNANT DISEASES INDUCED BY THE HPV TYPES TARGETED BY THE VACCINE. THE PREVENTION OF THE MALIGNANT DISEASE IS INFERRED. THE BASIS FOR THAT INFERENCE IS EXACTLY THE SAME AS WHAT’S USED FOR CERVICAL CANCER SCREENING, SO I WOULD SAY IT’S ON A PRETTY FIRM BASIS. SECOND GENERATION VACCINES WITH ACTIVITY AGAINST THE BROADER RANGE OF TYPES SHOULD ACHIEVE AN EVEN GREATER REDUCTION IN HPVASSOCIATED DISEASE, AND THE HIGH I HUE KNOW GENICITY OF THE VACCINE IMPLIES IT SHOULD BE POSSIBLE TO IP DUES LONG TERM PROTECTION WITH FEWER THAN THREE DOSES.

THANK YOU VERY MUCH FOR YOUR LOVE TO HEAR YOUR COMMENTS AND QUESTIONS. APPLAUSE gtgt HI. THANK YOU FOR YOUR TALK. I WAS AROUND WHEN YOU INTRODUCED THIS, I FOLLOWED THE POLITICAL CHAOS GOING ON WITH THIS. QUICK QUESTION, AND IT’S MORE YOUR THOUGHT, IS THE AFFORDABLE HEALTHCARE ACT GOING TO COVER IMMUNIZATIONS FOR VARIOUS AGENTS AND DO YOU HOPE THAT NOW THAT IT’S GOING TO BE COVERED, AND THERE’S NOT THE SAME MEDIA BACKLASH THERE WAS WHEN YOU FIRST CAME OUT, DO YOU HOPE THERE WILL BE MORE SUPPORT AND.

MORE PEOPLE GETTING VACCINATED gtgt SO THE UNITED STATES HAS A VERY INTERESTING WAY OF ORGANIZING VACCINATION. WE HAVE A FEDERALLY SPONSORED PROGRAM CALLED THE VACCINE FOR CHILDREN PROGRAM, THE WHICH PROVIDES ABOUT 40 OF THE VACCINE TO CHILDREN UNDER THE AGE OF 18. THE HPV VACCINE IS AMONG THE VACCINES THAT ARE OFFERED THROUGH THE VACCINE FOR CHILDREN’S PROGRAMS. AND SO CHILDREN FROM POOR FAMILIES THAT ARE MEDICAIDELIGIBLE, AND THERE ARE A NUMBER OF OTHER CRITERIA, ALL CAN GET THE VACCINE FOR FREE. IT ACTUALLY COSTS THEM LESS THAN IT COSTS THE CHILDREN OF PEOPLE.

WHO HAVE PRIVATE INSURANCE BECAUSE THE PRIVATE INSURANCE DOESN’T ALWAYS PAY FOR THE COST OF THE VISIT. THEY PAY FOR THE VACCINE BUT THEY DON’T ALWAYS PAY FOR THE COST OF THE VISIT. IN PRINCIPLE, WITH THE AFFORDABLE CARE ACT PREVENTION COSTS ARE SUPPOSED TO BE FULLY COVERED. WHETHER THAT’S GOING TO BE A BIG DIFFERENCE IN THIS INSTANCE, I’M NOT SURE. MOST WOMEN GET CERVICAL CANCER SCREENING, AND WHETHER THE AFFORDABLE CARE ACT YOU KNOW, WHETHER THE AFFORDABLE CARE ACT WILL HAVE A BIG IMPACT ON THAT, I DON’T REALLY KNOW.

IN PRINCIPLE, IT MEANS THAT ANY WOMAN WHO WANTS TO GET SCREENED SHOULD NOT NEED TO PAY FOR IT, BUT I JUST IT’S HARD TO KNOW, THE WOMEN WHO A PIE PROPORTION OF WOMEN WHO DEVELOP CERVICAL CANCER ARE WOMEN WHO HAVE NOT BEEN SCREENED, AND OBVIOUSLY LACK OF ACCESS IS ANG ISSUE. ONE WOULD HOACH THAT THER HOPE THAT THERE WOULD BE LESS IT WOULD BE EASIER, BUT IT REMAINS TO BE SEEN. gtgt YOU HAD COMMENTED BEFORE ON THE OF SCREENING, AND WE HEARD IN MR. CANTRELL’S CASE.

THAT MAYBE WHEN THE EARLIEST DETECTION WAS DUE TO HIS BREATH AND HIS WIFE COULD SMELL A DIFFERENCE. COULD YOU COMMENT ON WHAT RESEARCH THERE MAY BE FOR USING ODOR AS A FORM OF DETECTION FOR HPV AND FOR VERY COSTEFFECTIVE SCREENING gtgt I HAVE NO SPECIFIC INFORMATION ABOUT THAT. I CAN’T COMMENT ON IT. gtgt I THINK THAT’S A NONSPECIFIC MANIFESTATION OF HEAD AND NECK CANCER. IT’S JUST AS COMMON TO HAVE THAT IN HPV NEGATIVE AS HPV POSITIVE, AND IT’S BECAUSE THE BACTERIA THAT COLONIZE PROBABLY GROW QUITE WELL.

INAUDIBLE gtgt I JUST HAVE TWO QUESTIONS. ONE IS I THINK MAYBE THE RATIO FOR MEN TO WOMEN IS EVEN HIGHER TODAY THAN 31 THAN IT USED TO BE. I WAS JUST WONDERING, IS PRIOR VAGINAL CERVICAL VACCINE IN ANY WAY PROTECTIVE, OR IS THAT A POSSIBLE EXPLANATION TO EXPLAIN THE DIFFERENCE AND MY SECOND QUESTION WAS INAUDIBLE gtgt IT’S ONLINE. gtgt I KNOW, BUT NOTICED ANY INAUDIBLE gtgt SO THE ANSWER TO THE FIRST QUESTION IS THAT WE DID STUDIES ACTUALLY BACK IN THE 90s THAT DEMONSTRATED THAT MALES HAD A.

MUCH LOWER RATE OF BEING ANTIBODYPOSITIVE THAN FEMALES, AND WE SUSPECT THAT IT IS THE CAUSE OF THE GENITAL INFECTION IN THE WOMEN, SOMEHOW LEADS TO THEY’RE MORE LIKELY TO DEVELOP ANTIBODIES WHICH WE TAKE TO BE AN INDEX OF IMMUNITY. AND SO I THINK IT’S CERTAINLY POSSIBLE THAT IMMUNITY IS SOMEWHAT PROTECTIVE, AND THAT WOMEN ARE MORE PROTECTED THAN MEN ARE. BUT THIS IS SPECULATION. gtgt YOUR SECOND QUESTION REALLY IS ONE OF HPV TYPE PLACEMENT, AND THUS FAR, THERE IS NO EVIDENCE THAT THERE HAS BEEN HPV.

TYPE REPLACEMENT AND MY MEDICAL EPIDEMIOLOGIC COLLEAGUES, THEIR NOAX IS THAT THESE VIRUSES TEND TO BEHAVE RELATIVELY INDEPENDENTLY ONE FROM THE OTHER, BUT CLEARLY BOTH COMPANIES ARE FOLLOWING UP POPULATIONS IN SCANNED 2345EU6 YA FOR A MINIMUM OF 15 YEARS AND WILL BE LOOKING AT THAT QUESTION, AND IN COSTA RICA, WE’RE ALSO DOING A LONGTERM FOLLOWUP LOOKING AT THAT ISSUE AS WELL. gtgt ASSUMING THERE’S NO DECREASE IN ANTIBODY TITERS OR IMMUNITY, DO YOU THINK A POSSIBLE SOLUTION TO THE SOCIAL BACKLASH COULD BE OFFERING THE VACCINE MAYBE AT A.

YUFNYOUNG AGE, AT 3 OR 4 gtgt THIS IS CERTAINLY A THIS IS A POTENTIALLY VIABLE POSSIBILITY, BUT THERE ARE CURRENTLY TWO PROBLEMS. THE FIRST IS THAT IT WOULD TAKE THAT MUCH LONGER BEFORE YOU WOULD SEE AN IMPACT FROM THE VACCINE, AND FROM A COSTEFFECTIVENESS POINT OF VIEW, THAT MIGHT BE A REDUCTION, OKAY THE SECOND IS THAT WE HAVEN’T FOLLOWED PATIENTS WHO HAVE BEEN VACCINATED FOR LONG ENOUGH TO KNOW WHETHER IT WOULD LAST LONG ENOUGH. WHAT I THINK ONE COULD MAYBE MORE SAFELY ENVISION IS MAYBE THE FIRST DOSE, IF YOU WERE.

GOING TO BE DOING TWO DOSES, YOU MIGHT GIVE THE FIRST DOSE AT THAT AGE AND THEN A BOOSTER DOSE AS AN ADOLESCENT, BUT AGAIN, WOULD YOU GET INTO THE YOU KNOW, GET INTO THE SAME SOCIAL PROBLEM. gtgt YOU’VE BEEN VERY PATIENT. gtgt TWO QUICK QUESTIONS. gtgt IT’S YOUR PUNISHMENT FOR SITTING IN THE BACK. gtgt WHAT DO YOU KNOW ABOUT THE EFFICACY IN WOMEN WHO ARE EXPOSED TO HPV 16 OR 18 PRIOR TO GETTING THE VACCINE I DON’T KNOW WHETHER THERE’S A WAY TO KNOW THAT. gtgt SO IN COSTA RICA, MY.

COLLEAGUES LOOKED AT THE NATURAL HISTORY OF THE WOMEN WHO WERE VACCINATED EITHER WITH THE VFK VACCINE OR WITH THE CONTROL WHICH ACTUALLY WAS HEPATITIS A VACCINE AND LOOKED AT THE WOMEN WHO HAD PREVALENT INFECTION AT THE TIME OF VACCINATION. AND THERE IS NO DIFFERENCE IN THE RATE AT WHICH THEY CLEAR, OKAY SO THERE’S NO STRONG SUGGESTION THAT THERE IS A CHANGE IN THE NATURAL HISTORY OF PEOPLE WHO ARE PREVALENTLY WHO ARE PREVALENTLY INFECTED, OKAY, AND MERCK HAS SAID THE SAME THING, ALTHOUGH I HAVEN’T SEEN IT.

PUBLISHED IN THE SAME DETAIL AS WITH THE GFK VACCINE. gtgt MEN, OLDER MEN RECEIVING THE VACCINE, SAY BETWEEN THE AGES OF 20 AND 30 gtgt SO THE ISSUE OF THE VACCINE, THE MERCK VACCINE IS APPROVED FOR MALES UP THROUGH AGE 26, I GUESS. 25 OR 26. SO ABOVE THAT AGE WOULD BE OFF LABEL. THERE ARE PEOPLE WHO RECOMMEND AN OFF LABEL USE BECAUSE WHEN YOU LOOK AT THE PROFILE OF THE APPARENT AGE OF ACQUISITION OF ORAL HPV INFECTION, IT LOOKS AS THOUGH MANY MEN ARE REQUIRING REQUIRING.

ORAL HPV WHEN THEY ARE IN THEIR 20S OR EVEN IN THEIR 30s, SO ON THAT BASIS, IT HAS BEEN SUGGESTED. gtgt SO IF NEWBORNS ARE BORN OF A MOTHER THAT HAS INFECTION, NEWBORNS DON’T HAVE ANTIBODIES, DO THEY IF THEY DO, WHY DON’T NEWBORNS GET THE DISEASE gtgt SO THE FIRST POINT IS THAT IGG ANTIBODIES DO GO ACROSS THE PLACENTA AND AND A PROPORTION OF THE WOMEN HAVE IGG ANTIBODIES. THE SECOND IS THAT THE INCIDENCE OF GENITAL HPV INFECTION IN PREGNANT WOMEN IS VERY HIGH, BECAUSE IT ACTUALLY TENDS TO GO.

UP BECAUSE OF THE RELATIVE IMMUNE SUPPRESSION OF PREGNANCY, PROBABLY YOU GET REACT VAITION, VAITION, AND AFTER DELIVERY, THE PERCENTAGE OF HPV POSITIVITY ACTUALLY GOES DOWN. BUT THERE IS POTENTIALLY SERIOUS INFECTION KNOWN AS LARYNGEAL PAPILLOMATOSIS OR RECURRENT RESPIRATORY PAPILLOMATOSIS THAT OCCURS IN CHILDREN, AND A REASONABLE PROPORTION OF THOSE CHILDREN ARE BELIEVED TO ACQUIRE THE INFECTION DURING DELIVERY THROUGH THE BIRTH CANAL. ONE POTENTIAL UTILITY OF THE VACCINE IS THAT IT SHOULD, AT LEAST FOR THE MERCK VACCINE, IT SHOULD VIRTUALLY ELIMINATE THIS DISEASE. THE PROBLEM IS THAT IT’S NOT SO.

MUCH OF A PUBLIC HEALTH PROBLEM BECAUSE THERE WERE MAYBE A THOUSAND CASES IN THE UNITED STATES PER YEAR, AND SO IT’S DIFFICULT TO STRONGLY ADVOCATE FOR THAT, IN ADDITION, IT WOULD BE AN OFFLABEL USE OF THE VACCINE TO VACCINATE FOR THAT REASON. OF COURSE IT’S PERFECTLY FINE TO VACCINATE WOMEN WHO ARE NOT PREG NAN, WHO ARE OF CHILD BEARING AGE, THAT’S PERFECTLY LEGITIMATE, BUT IT’S NOT AN FDAAPPROVED USE. gtgt INAUDIBLE THEY SHOWED ACTUALLY THAT THERE’S THOSE TWO PEAKS ACTUALLY OF ORAL INFECTION, AND ONE IS.

ACTUALLY MORE LIKE IN THEIR 40s, RIGHT AND I JUST WONDER, IF YOU DON’T GET A STRONG IMMUNE RESPONSE FROM SEXUAL EXPOSURE TO CANCER INAUDIBLE gtgt THIS IS A LITTLE BIT OF AN INSIDE BEAS BALL KIND OF BASEBALL KIND OF DISCUSSION, BUT AND HER COLLEAGUES HAD A PAPER LOOKING AT SINGLE TIME POINT PREVALENCE PUBLISHED IN THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION ABOUT TWYEARS AGO, AND WHAT WAS SHOWN WAS THIS BIPHASIC CURVE SO THAT MEN WHO ARE IN THEIR WIT 50s HAD A HIGHER PREVALENCE THAN MEN WHO WERE IN.

THEIR 40s. I THINK THAT IT REMAINS TO BE SEEN WHETHER THIS IS ATTRIBUTABLE THERE WERE SEVERAL POTENTIAL EXPLANATIONS. ONE IS IT’S SIMPLY A COHORT EFFECT. IF YOU HAD BEEN ABLE TO SAMPLE THOSE MEN IN THEIR 50s, YOU SAMPLED THEM IN THEIR 40s, THEY WOULD HAVE BEEN HIGH THEN TOO. ANOTHER POSSIBILITY IS THAT IT’S ACTUALLY REACT VAITION OF A FORMER INFECTION WHERE YOU HAVE HAD CLINICAL RESOLUTION BUT YOU WERE STILL VIROLOGICALLY POSITIVE, SO YOU NOW HAVE A REACT VAITION. THEN THE THIRD POSSIBILITY IS A NEW EXPOSURE.

SIMILAR KIND OF BIPHASIC PREVALENCES HAVE BEEN SEEN IN SOME COUNTRIES IN WOMEN AT THE CERVIX AND YOU GO THROUGH THE SAME KIND OF ISSUES AND IT REALLY HASN’T BEEN RESOLVED. gtgt I HAVE A QUICK QUESTION ON HPV TESTING, A LOT OF THE STATISTICS ARE BASED ON TESTING POSITIVE OR NEGATIVE FOR HPV, AND WHAT DO YOU THINK IS THE TRUE POSITIVE AND TRUE NEGATIVE FALSE POSITIVE AND FALSE NEGATIVE TESTING FOR HPV, BOTH GENITAL AS WELL AS ORAL WHAT DO WE KNOW ABOUT FALSE POSITIVE AND FALSE NEGATIVE.

TESTING gtgt SO IT MAY BE A QUICK QUESTION, I’M NOT SURE IT’S A QUICK ANSWER. I THINK FIRST LET’S DEAL WITH GENITAL INFECTION. OKAY WHEN FALSE POSITIVE, SHE DOESN’T MEAN YOU WERE HPV POSITIVE BUT YOU’RE NOT INFECTED. SHE MEANS YOU’RE HPV POSITIVE BUT YOU DON’T HAVE PRECANCER. OKAY LET’S JUST UNDERSTAND, THE TEST IS VERY SPECIFIC IN TERMS OF DETECTING HPV. THERE WERE VERY FEW FALSE POSITIVES IN THE SENSE THAT YOU’RE POSITIVE FOR THE TEST BUT YOU’RE NOT REALLY INFECTED. BUT THERE ARE MANY PEOPLE WHO ARE INFECTED BUT DON’T REQUIRE.

TREATMENT BECAUSE AS I MENTIONED, THE NATURAL HISTORY FOR MOST INFECTIONS IS THEY JUST GO AWAY. YOU DON’T NEED TO BE TREATED. SO THIS BRINGS UP THE ISSUE OF FALSE POSITIVE IN THAT SENSE, AND A LOT OF PEOPLE ARE WORKING ON WHAT ARE CALLED ANCILLARY TESTS, SO ONE OF THE FAVORITE ANCILLARY TESTS IS P16, WHICH DR. VON WAES MENTIONED IS POSITIVE IN A VERY HIGH PROPORTION OF HPVPOSITIVE CANCER BUT ALSO IN A HIGH PROPORTION OF HPV POSITIVE PRECANCERS. SO THAT’S ONE POSSIBLE TEST. ANOTHER TEST THAT IS BEING.

EXAMINED IS METHYLATION. THERE IS METHYLATION OF SPECIFIC PARTS OF THE HPV GENOME WHICH SEEMS TO BE PREDICTIVE OF WHETHER OR NOT YOU ARE GOING TO HAVE WHETHER OR NOT YOU HAVE PREMALIGNANT DISEASE. SO THOSE ARE THE KINDS OF THINGS IN TERMS OF FALSE POSITIVE, WHAT’S BEING DONE WITH IT. FALSE NEGATIVE. THE HPVBASED TESTING IS REMARKABLY GOOD AT ELIMINATING FALSE NEGATIVES, AS LONG AS YOU HAVE A VALID TEST, THAT IS SOME KIND OF DNA TEST, THE DNA IS REALLY THERE IN A TEST. THERE’S ALMOST NOTHING THAT.

HAPPENS IN THE NEXT 10 YEARS. YOUR CHANCES OF BECOMING YOUR CHANCES OF DEVELOPING HIGH GRADE CERVICAL DYSPLASIA ARE VERY LOW. THIS IS ONE OF THE REASONS WHY WITH COTESTING, THE RECOMMENDATIONS NOW OF THE U.S. PREVENTIVE SERVICES TASK FORCE IS EVERY FIVE YEARS, IF YOU HAVE CYTOLOGY PLUS HPV TESTING. WHEREAS CYTOLOGY ALONE IS EVERY THREE YEARS. SO THAT TAKES CARE OF BELOW THE WAIST. NOW, IN THE MOUTH, THE PREVALENCE OF INFECTION IS MUCH, MUCH LOWER, AND I THINK THERE’S JUST NOT BEEN THAT MUCH EXPERIENCE. AND I THINK THE PREDICTIVE VALUE.

IS JUST NOT THAT GREAT. SO IN THAT SENSE, THERE WOULD BE A LOT OF FALSE POSITIVES. ONE THING THAT I DIDN’T MENTION IS THAT THERE WAS A RECENT STUDY WITH DATA IN EUROPE USING HPV 6 ANTIBODIES AS A SERUM TEST, AND IT’S DEEMED TO BE HIGHLY PREDICTIVE OF PEOPLE WHO WERE DESTINED TO DEVELOP WHAT ARE PRESUMED TO BE HPVPOSITIVE OROPHARYNX CANCER, BUT MORE RESEARCH NEEDS TO BE DONE TO TRY TO LOOK AT THOSE CORRELATIONS BECAUSE A LOT OF THEM ARE INFERENTIAL RATHER THAN STRONGLY EVIDENCEBASED. THANK YOU.

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