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The p r eve n t ion of cervicalin t r aep i the l a l neoplasiaGlyn TealePrevention strategies for cervical intraepithelial neoplasia (CIN) haverelied largely on secondary prevention by detection using cervicalcytology. Recent developments include a potential role for liquid-based cytology, human papillomavirus (HPV) testing, th e prospect ofmolecular markers of CIN and a possible role fo r optoelectronicdevices. Primary prevention by vaccination shows promise althoughthe exac t direction of vaccination programmes remains unclear.General health measures such as smoking reduction may improve CIN;improved sexual health may reduce HPV exposure and th e risks of
Chlamydia trachornatis, now recognised as a risk for CIN. The role o fdietary manipulation and the benefit of male circumcision are beinginvestigated.
Introduction
M o r h ririwrioe, as cervical cancer wasdescriptively called in the 19th century, affectedover 466 000 wonien in the year 2000, 79% ofcases occurring in developing countries. ' Itspreinvasive phase, cervical intraepithelialneoplasia (C IN ), annually affects in excess of40
million women worldwide. Several preventionstrategies exist to reduce the magnitude of thisproblem. Thi s ar t ic le reviews currentdevelopments in the prevention ofCIN.
Aetioloqy of CIN
There is overwhelming epidemiological andexpe r imen ta l ev idence suppor t ing theaetiological role of certain high-risk hu ma npapillomavirus (HPV) types (HPV-16.18.31.33.35, 45, 51, 52,58 59) in the development ofCIN and cervical cancer. Ov er 99% o f cases ofcervica l cancer conta in HPV DNA. ' Most of theidentified risk factors for CIN and cervicalcancer (Table 1) are now thoug htto be surrogatemarkers o f H PV infec t ion .
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Keywordscervicali n t r a e p i t h e l i a lneoplasia (CIN),h u m a npap i l lomavi rus(HPV), prevention,screening, vaccines.
The HPV story
The re are over 130 types of these small , highlyconserved, nonenveloped DNA viruses. Maturevirus particles are approximately55 nni indiameter and have a 72-sided icosahedral outercapsid coat composed oftwo structural proteinsL1 and L2 (Figure 1). Con taine d within the
capsid coat is the viral genome which is adouble-stranded circular D N A approximately7.9 kilobases in length. ' Each genome can bedivided into seven early (E) andtwo late (L)regions (Figure2 ) .Reg ions E6 andE7 code foroncoprote ins tha t in ter fere wi th ce l l cycleregulation by inhibit ing the activity of thet u m o u r s u pp r es so r s p 5 3 a n d p R b(retinoblastonia protein). T h e disruption o f cellcycle contro l i s requi red for HPV vi r ionpropagation but can inadvertently result insquanious cell dysplasia.I t has been estimatedtotake in excess of six yearsto develop CIN3 afterinitial infection andto take on average13 yearsto develop cervical can cer from nor ma l cytology.Approximate ly 30% of CIN3 lesions willprogress to cancer within ten years. ' Author details
Table 1 R i s k fac tors for ccrviciil cancer arid C I N
Multiparity FRANZCOG Consultant ObstetricianCigarette sinoking an d Gynaecologist She pparton
Cotnbined or21 contracept ion/rrdi~ced condoin iisr Victoria Aus tralia. ema il:
I l i e t x y f x t o r s
Early age 3t first intercourse (I6 years or yo unger)A history of multiplr wxudl partnersHl'V infec tion, chlamydia or other sexually transmitted diseasesThc presencc of other genital tract neoplasiaPrevious CIN Glyn R Teale BSc I D R C P M R C O G
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Figure 1 Computer enhanced electonmicrographimage of an HPV viron showing the structure ofthe capsid protein coat
Seconda ry prevent on s t rate q es
Figure 2 Relative size andlocation of the HPV genes
within the 7.9 kilobasecircular DNA
Prevention strategies for C I N have,to date,largely relied on a secondary-level approach(Table 2). T h e apparently lo ng preinvasive phasefacilitates effective screening, most com mo nly byregular cytology. A well-organised three-yearlyscreening programme is able to decrease theincidenc e of cervical cancer by over90%.According to the Imperial Cancer ResearchFund (ICRF) cervical screening preventsbetween 1100 and 3900 cases of cervical cancereach year in the UK, largely by detectingpreinvasive lesions.' However, this approach isaconsiderable financial and logistical burdentothe NHS, costing annually in excess ofA140 million, employing over 100 000personnel who have to cope wi th overfou r million smears each year. O n a global scalemany countries are unableto accommodate thesubstantial costsof providing for the associatedinfrastructure, manpower, consumables, followup and surveillance of an effective screening
strategy. T h e World H ealth Organ izationrecognises that cytology screening programmesare simply not feasible in many countries.'
Visual inspection-based screening approachesmay present fewer logistical problems todeveloping co untries. Th e most promising ofthese involves visual inspection with acetic acid.After inserting a speculum, acetic acid is appliedto the cervix. Tho se w ith acetow hite lesions arereferred for interven tionor furth er investigation.
This requires a limited amount of training, butavailable studies report negative predictive valuesof over 95%. There are three large, continuingintervention trials in India to evaluate theeffectiveness of visual inspection with acetic acid.
Ta b l e 2. Levels of d i sease p reven t ionLevel Aim
Prinlary preventionSecondary prevention
To prevent the onset ofa disease.To halt the progressionof adisease once it is established,generally by early detectionfollowed by prompt effective
treatment.This is generally theapproach of screeningprogrammes.To rehabilitate people with anestablished diseaseto minimiseresidual disabilities andcomplications.
Tertiary prevention
Newer approaches t secondaryprevention
Cervical cytology has come under attackbecause of a growing awareness of the test'simperfections, in particular its false negativity. Inan effort to improve the sensitivity ofconventional screening several options are beinganalysed.
ew cervical smear techniquesFluid-based, thin layer processing of cervicalsamples (e.g. Th inp rep @ ,Cytyc Corporat ion,Boxborough, MA) at temptsto reduce samplingerrors and improve specimen adequacy bysuspend ing cervical cells in a liquid solution. O nreaching the laboratory the solution is applied
to a slide so that cells form a thin layer,theoretically making it easierto successfullyevaluate cervical cells.' The clinical impact of
1 Genome 7904
L1I 2 L . l
Capsid proteins
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these systems is currently under investigation.Although advantages in terms of improvedsensitivity and speed of processing are expected,the technique could add in excess ofA18 million to the cost of the screeningprogram me in England and Wales. Furth erm ore,initial enthusiasm for the technique has beenfollowed by increasing scepticism. The exactrole of these techn iques remains unclear.
H P V testingThe association of H P V w i t h C I N h a sstimulated a plethora o f reports on the benefit ofHP V test ing. Th e most comm only usedtechnique is the commercially available HybridCapture I1 HPV test (Digene Corporation,Gaithersburg, MD).This test can reliably detectabatch of high-risk HPV types ina matter ofhours.
The most pronlising role for HPV testing mayinvolve triaging o f low-grade smear abnormalities.The re are over250 000 low-grade smears per yearin the U K ; the majority are no t associated withsignificant preinvasive disease. HPV testing inASCUS smears (abnormal squamous cellsofundetermine d significance oughly equivalenttoborderline nuclear abnormalities) can increase thesensitivity of detecting women with high-gradeCIN and could reduce the number of womenreferred to colposcopy by approximately50%.Unfortunately 83 of women with mild
dyskaryosis test positive for high-risk HPV,limiting the usehlness of the test in this smeargroup. ' Data from U K trials such as the IC RF -funded HPV in Additionto Rou tineTesting study(HA RT ) are irnnunent.
At present the exact role of HPV testing withinthe screening programme remains uncertain.Only a small percentage of women diagnosedwith HPV at a single point in time will everdevelop CIN (perhaps2-3%). However, up to75 of women will be affected by HP Va t sometime, many of them only transiently; upto 70of those initially diagnosedas HPV positive testnegative within two years. Furthermore, UKdata have suggested that our understanding ofthe natural history of HPV infection anddevelopment of C IN may be flawed. A largeprospective study involving six-monthly followup of teenage girls found that40 of those w hodeveloped an abnormal smear were HPVnegative and33 only tested positive at the samevisit as the cytological abnorma lity was detec ted.The median time to diagnosis of high-gradeC I N was only three years in this study.
Real-time optoelectronic devicesA number of optoelectronic devices are
current ly un der development . T he most REVIEW
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established is the Truscana' (E thic on Ltd,Edinburgh, UK) (formerly called thePolarprobe).I t is a portable device which, when
2003;5:21-7pplied to the cervix, delivers low-level electrical
and optical signals and detects th e resultant tissueresponse. Th ese tissue signatures are co mparedagainst a databank in the system and a report isgenerated categorising the cervix as normal,low-grade o r high-grade CIN . Tests on theclinical usefulness of this device are continuing.
Molecular markersThe re is a bewilde ring array of data accruing o nthe use of a range of molecular markers in thesecondary prevention o f CI N . Most o f theseutilise the rou tine smear and subject it to furth eranalysisfor various proteins, in the hope that thismay increase th e overall sensitivity At the presenttime none is sufficiently developed for clinicalapplication. Furthermore, although somemarkers, such as telomerase activity, have sho wninitial promise , follow-up data are often lessoptimistic.'' For now, molecular based screeningtechniques only remain research based.
Pr imary p reven t ion of CIN: HPVvaccine de ve lop me n t
Data on the central role of HPV in thepathogenesis of cervical neoplasia havestimulated efforts at primary prevention by
vaccination. As well as theoretical reductions inthe incidence of CIN and cervical cancer,prophylactic HPV vaccines could potentiallydecrease the incidence of genital warts, the mostco mm on sexually transmitted disease ( ST D), andof several other cancers (Table3).
Table 3 . HPV-associated cancers
'Ifrpe of cancer
Cervical 99.7Anal 8 5 4Vulval, vaginal, penile 50.0
Percentage of casesassociated with HPV
Ompharyngea l 20.0Laryngeal 10.0
Historically, HPV vaccine development has beenhampered by the fact that there is no efficientway of propagating HPVin v i m and the virusdoes not cause animal disease, limiting animalresearch. A major breakthrough came w ith th ediscovery that the capsid proteinsL1 and L2 (orL1 alone) are ableto self-assemble into virus-likeparticles (VLPs). The se VLPs are structurally
identical to native H PV, although they lack theviral DNA core and thus also lack theoncogene s. Most usefully they are ableto induce
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Strategy Principle Comm ents
Virus-like particles VLl’s closely resenible native HP V particlesand include the conformational epitopes thatinduc e virus-neutralising antibodies.
Mainly prophylactic in nature although recentevidence suggests that they may be abletoinduc e cell-mediated inimunity.” Curre ntresearch is analysing the prospects of in ducin gniucosal IgA. lntranasal and intragastricapplication of purified VLl’s has also beenshown to be effective at generating bothseruni I < and genital tract IgA in niice.
Recombinant livevector vaccines
Use of whole organisms produces a strongimm une response. HI’V genes are addedtobacteria or virusesto create a live vectorvaccine.Vectors should b e capableof infectinghum ans w itho ut causing clinical illness.
Encouraging phase andI I results from UKclinical trials on a therapeutic vaccine calledTA-HPV (live reconibinant vaccinia virusthat expresses E6 andE7 from HI’V-16 andHI’V-18); developed by CantabI’harmaceuticals plc (Cambridge,UK).
Protein and peptidevaccines
HPV genes are inserted into anotherorganisni e.g. yeast) to produce largequantities of the chosen protein or peptidefor insertion in to huma ns. Generally safe,cheap and easy to manufacture.
Subu nit and peptide vaccines relyon geneticengineering techniques to produce fragmentsthat can evoke an ininiune response.Trialsusing a fusion protein o f tw o HI’V-6 proteins(L2 and E7) given intramuscularly ‘ireunderway.
‘Naked’ DN A
vaccines
Generation of bacterial plasmids that contain
HPV genes. In humans these plasmids wouldlead t o th e production of selected HI’Vantigen, which would serve as a powerfulininiunogen.
Am ong the newest approachesto vaccine
developnient.They induce cell-niedidted aswell as antibod y-med iated ininiunity, arelikely to be cheapto produce and distributeHowever. safety is currently a con cern:Plasniid D N A migh t induce host cellniutations. disrupt cellular genes or ind uceanti-DNA antibodies.
Still at an early stage of develop men t. Possibleadvantages include stiniuldtionof the niucosalimmune system and inexpensiveto produceand distribute.
Edible vaccines Plant biotechnologists have developed plantssuch as potatoes, carrots and lettuce thatcontain genes for HI’V.These geneticallyengineered plants produce and accumulatedisease antigens in their tissues. Th eir fruitsand vegetables are then ableto induce anininiune response.
Further information can be found in Kols and Sherris .”
virus-neutralising antibodies. In animal studiesuse of VLPs suggested 90-100%1 protectionagainst species-specific papillomaviruses. Clinicaltrials (phase I) have shown complete regressionof genital warts in25 ou t o f 33 patients using anHPV-6 L1 VL P” An HPV-11 VLl’ vaccineproved to be highly immunogenic and welltolerated”, and anHPV- 16 VLP vaccine has also
been similarly shownto produce high levels ofprotective antibody, with titres that w ere 40-foldhigher than those observed in natural infection.”A vaccine efficacy trial is currently underway inGuanacaste Province,Costa Rica.
Altho ugh L1 VLP vaccines seenito be goodcandidates for effective protective im munity,L1capsid protein is only expressed late in the virusl ifecycle . Therefore , H P V may remainunaffected by antibodies as i t evades theimmune system within the lower layers of theepiderniis.This has ledto concern that L l VLPvaccines may be unable to effectively clearexis t ing HPV infect ion in a l l women.Therapeut ic immunity ( i .e . eradicat ionof
existing infection or C IN ) may be obtained bythe generation of cytotoxicT lymphocyteresponses against early ge ne p rodu cts. Th is hasled to the develop men t of so-called c hiniaer icVLPs. Thes e co mpr ise of L1 capsid proteins,which are fused to early gene products suchasE6 o r E7. Theoretically these chiniaericVLPscould generate a humo ral (antibo dy) response
to viral capsids for preventing HPV infection,together wi th a cytotoxic T lymphocyteresponse versus HPV early gene products foreliminating infected cells. Initial results frommouse models have found that such chiniaericVLPs have good immunogenicity and patientt ria ls are underway.IH O th er therapeut icapproachesto H PV vaccines are suniniarised inTable 4.
Problems with vaccinationprogrammes
T h e success of vaccination programmes againstacute childh ood viral diseases has led toa generalassumption that once an effective vaccine has
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been developed its use will be straightforward.This may not be t rue for HP V vaccinat ion .
I t is unclear at present against whic h H P V typesto vaccinate and whether the vaccine should beniono- or multivalent. A monovalent vaccineagains t HPV-16 a lone might theore t ica l ly
prevent approximate ly 50% of cervica lcarcinomas. However, this gain may b e offset bythe inadvertent increase in infections by othertypes that are also oncogenic with the result thatthere would b e n o appreciable decrease in can cerrate overall.Use o f a multivalent vaccine wouldincur cos ts tha t may make the vaccineinaccessible to the developing world, the veryarea where an efficient vaccine is most needed.Inclusion of at least on e non-o ncogenic type,e.g.HPV-6, (whic h causes the majority of genitalwarts) would address the public health issueofthe high in cidence o f genital warts. This mightalso make the vaccine more attractive forwomen, especially as it would prevent a moreimmediate disease than cervical cancer and maymake the vaccine attractive to nien whoseimm unity would be beneficialto break the cycleof sexual transmission. There is , however,evidenc e that suggests that HP V infections maybe antagonistic;a history o f genital warts mayprotect a woman from gett ing cervical cancerand serological evidence o f previous HPV-6 andHPV-11 infection has also bee n associated wit haredu ced risk of HPV-16-associated cervical
carc inogenes is. Inc luding low-r isk H P Vprotection might reniove this antagonism withuncertain and potentially serious consequencesfor the proliferation o f oth er high-risk serotypesnot included.
I t is unclear who should be vaccinated againstHPV and how the vaccine will be perceived.Prophylactic vaccines would ideally be giventoprepubescent girls so that they are protectedbefore sexual experienc e, presum ing they havenot been infected vertically, which is knowntooc cu r occasionally.”’ Are the public readytovaccinate children against sexually transmitteddiseases? T h e stignia that remains aro und S TD smay prevent wom en f rom enter ing HP V vaccinetrials, not wantingto be perceived as belongingto a high-risk group. Perhaps of greater c once rnis t he r i sk t ha t women who have beenvaccinated against HP V will believe that they arefully protected from ever getting cervical cancerand will n o longer seek routine smears. T h eHPV vaccine, however, will not protect againstall high-risk HPV types and may not offerlifelong protection.
In developed countries there is evidencetosuggest that over80% of won ien wou ld wan t t he
vaccine . Such a f igure contras ts wi th theexpe r i ence o f deve lop ing coun t ri e s wherevaccinat ion programmes for adul ts a retraditionally po or yellow fever vaccinationcoverage for adults in c ountries w here the diseasehits hardest is traditionally less than 2 0% .Thu s itis qui te possible that th e organisational problems
that h inder cytology screening programmesmi ght also preclude th e success of vaccinationprogrammes.There is also the issueof cost.
Primary prevention bybehavioural changes
Sexual behaviour
Many studies have shown that cervical cancer isvirtually unknown in virgins and that sexualintercourse isa prerequisite for the develop mentof th e disease. Swedish data suggest that t he riskof seroconversionto HPV-16 increases linearly,wi th abouta 4% chance for each l ifetime sexualpar tner up to a plateau of about 32 a m o n gwomen with on average eight l ifet ime sexualpartners.”’ A l ong i tud ina l cohor t s tudy o fteenage girls found that none of the girlswithout sexual experience were, or became,seropositive for HPV-16 or-33; whereas 54% o fgirls with five or mo re partners w ere positive atsom e po in t i n t ime .” F rom a prevent ionperspective, efforts at sexual health education
could offer a chanc e of reducing HP V infection.Users of barr ier m ethods of cont racept ion areassociated witha r educed inc idence o f CIN.Th i smay be due to reduced acquisit ion of HPV,although there is an absence o f clear evidence forco nd om protec t ion agains t HPV, probablybecause H P V is ableto infect all genital skin andnot jus t th e area covered by a c o n d o m .Interestingly, any benefit o f co nd om usage mayhave more to do w i th the prevent ion of o therST Ds rather than HP V itself . Evidenc e has beenaccumulating suggesting that infection withClilaniydia trachoniatis may be a risk factor forinvasive cervical cancer.’’
More recent a t tention has focused on t he ro le ofthe male par tner in the development ofCIN.Penile lesions are frequently found in sexualpartners of women wi th C IN. Mostof theselesions are subclinical (i.e. only visible afteracetowhite staining) and are often associatedwith the presenceof high-risk HPV, indicatingthat male sexual partnersof women wi th CINmi ght c onst itute a reservoir for high-riskHPV.”I t is, therefore, interesting that evidence suggests
male circumcision is associated with a reducedrisk o f penile H P V infection an d a reduce d riskof cervica l ca ncer in the i r curren t female
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this evidence could be introduced into aprevention programme.
2003;5:21-7 Sin kin g
T he association of cervical cancer with sm oking
has been known for many years but has beencotnmonly regarded as attributable toconfounding by HPV infection, since smokinghabits and risk of acquiring HPV infection arelinked behavioural traits in some populations.However, evidence supports an independentassociation with smoking which is dosedependent.”.’“ Reducing or quitting smoking isassociated with improvements in CIN .”
Dietary considerations
Several case-control studies have investigated theeffects of various micronutrients on the risk ofC I N and cervical cancer. High dietary carotenearid possibly vitamins C and E are associatedwith reduced risk for cervical cancer in somestudies, but not in others.’” Low intake ofvitamin A has been shown in epidemiologicalstudies to be associated withCIN and cervicalcancer.’“ A randomised trial using locally appliedbeta-transretinoic acid demonstrated increasedregression of C IN 2 but not CIN 3.*” Folic acid(folate) deficiency may play a role in cervicalcarcinog enesis, possibly by fa cilitating
incorporation of HPV at a fragile genomic site.However, randomised controlled data of oralfolic acid as a chemopreventative agent havefailed to show a protective effect.”’
Combined oral contraceptive use
Som e data suggest an association betwe en C I Nand combined oral contraceptive use” but thismay be due to confounding f rom HPVinfection.” Wha tever the association it is probablyimpractical to suggest a role for reduction of
References
combined oral contraceptive use in theprevention o f CIN .
Conclusions
Cervical screening is an effective secondarypreventative approach to CIN and cervicalcancer. I t does, however, have its limitations interms of sensitivity, cost and organisationalburdens. Even in developed co untries upto 50of cancers may occur despite an adequate smearhistory.‘ Improvements in the screening systemmay come from newer technologies either incytology techniques, by the inclusion of HPVtesting or the use of molecular markers of CIN.HPV testing is being aggressively promoted butis not w itho ut its problems, in particular th e highprevalence of HPV infection, its transient natureand a lack of full understanding of its naturalhistory. Efforts to develop an effective HPVvaccine have comea long way an d are currentlybein g intensively investigated. How ever, there areunanswered questions. W hich HP V types shouldbe targeted? W h o should be vaccinated? Wouldwidespread vaccination lead to a significantreduction in the incidence o f CI N overall or willnon-targeted serotypes simply replace those thathave been removed ? T h e availability of a licensedHPV vaccine still appearsto be more than tenyears away. In the meantime prevention of CINmay be achieved by encoura ging wo me nto stopsmokin g and pro moting h eightened awarenessof
sexual health issues at a you ng age, priorto initialsexual expe rience. T h e role o f dietarymanipulation is currently unknown, as theevidence is conflicting, and the potential long-term impl icat ions of promoting malecircumcision needs further evaluation.
Acknowledgements
I am grateful to Professor David Luesley andDrTara Selman for their helpful comments in thecom pletion o f this manuscript.
I .
2.
3.
4.
5.
Ferlay J. Parkin DM. Pisani F cditors.GbIiomri 2000.Caiicrr liicidencr, Morraliry and f ’revalrti~eW>rldiiide.I A R C CaticerBasr No. 5 . Lyon: IARC I’ren; 1001.Walbooniers JM. Jacobs MV. Manor MM. Bosch FX.Kunmmer A, Shah KV, PI al. Human papilloniavirus isa necessary cause of invasive cervical cancerworldwide. J Pdiol 1999;189:12-9.Lor Alanios National Laboratory Bioscience Division.STD Sequence Databases. [http://hpv-web.lanI.gov/].Ostor AG. Natural history of cervical intraepithelialneoplasia: a critical renew. lnr Gyriecol Parliol1993;12:186-92.
Sasieni PD. Cuzick J, Lynch-Farmery E. Estiinatingthe efficacy of screening by auditing smear historiesof women with and without cervical cancer.TheNational Co-ordinating Network for Cervical
Screening Working Croup. Br J Cailrcr1996:73: 1001-5.Sankaranarayanan R udukh AM, Rajkumar R .Effective screening programmes for cervical cancer inlow- and middle-income developing countries. Bid1W d d Health O ~ a i i 001;79:954-62.Stoler MH . Advances in cervical screeningtechnology. Mod Par/iol2ooO;13:275-84.Moseley RP. aget S. Liquid-based cytology: is thisthe way forward for cervical screening? Cyroparhology2002;13:71-82.Soloinon D. Schiffman M,Tarone R. omparison of
three management strategies for patients with atypicalsquanmous cells of un determined significance: baselineresults from a randomized trial. Narl Cancer Lrsr2001 93:293-Y.
10.
11.
12.
13.
Human papillomavirus testing for triage of womenwith cytologic evidence of low-grade squamousintraepithelial lesions: baseline data from a randomizedtrial.The Atypical Squamous Cells of u ndete rminedSignificance/Low-Grade Squamous IntraepithelialLesions Triage Study (ALTS) Group.J Narl Camr Iiisr2000;92:397402.Woodman CB, Collins S, Winter H, Bailey A, Ellis J.Prior F r al. Natural history of cervical humanpapillomavirus infection in young women: alongitudinal cohort study. Lancer 2001;357:1831-6.Singer A.The polarprobe (TruScanTM) linical
perspectives. In: Monsonego J. editor. Global Cliallriifrojcewiral caticcr screeniii~ iid prevrnrioii C M E oiiriial ofGynecologic Oncolofy2ooO;14:3Y-40.Zhe ng PS. lwasaka T, Zhang ZM. Pater A, Sugiinori
26
-
8/18/2019 toag.5.1.21
7/7
H . Teloiiierase activity in I’apanicolaou smear-negativeexfoliated cervical cells anditr association w ith lesionsand oncogenic human papilloniaviruses.Gyiiecal Oiirol
14. Ng m HY. Ch cun g AN, Liu SS. Liu KL,Tsao SW.Tclonierase dssry and HPV16/18 typing as adjuncttoconventional cytological cervical cancer screening.
i l l r l ~ ~ l r r id 2002;23:87-Y2.Zhdng LF. Zh ou J. Chen S, Cai LL, Bao QY. ZhengFY, ci d HPV6b virus like particles are potent
iiiiniunogens without adjuvantin man. Vacniie2(HlO:18:IOSI-8.
16. EvansTG. Bonnez W.Kose I lC , KoenigS. DemeterL. Suzich JA.CI al A Phase 1 study ofa recombinantviruslike particle vaccine against humanpapilloinavirus type 11 in healthy adult volunteers.J/ I / ~ I Dis 2011 ;183: 1485-93.
17. Hdrro CD, I’angYY. ll od en RB. Hildesheini A.Wang2 Reynolds MJ, 01. Safety and immunogenicirytrial in adult volunteers of a human papillomavirus16LI virur-like particle vaccine.J Naf l Caii r r r I i i s f2001 93:2XCY2.Ru dol f MI? Nicland JD, DaSilva 1IM.Velders M P,Muller M, Greenstone HL.ef al I nduc t ion o f HP Vl6capsid protein-$pecific humanT cell responses byvirus-like particles. i d liein 19YY;380335-40.
I Y. Watts D H. K outsky LA, Holiiies KK. ColdmanD,Kuy pen J, KiviatN U f al. Low risk o f perinataltransmission of huma n papillomavirus: results fromaprospective co hort study. iii J Obsrrr C y i i c d
20. IMlner J . Kal l ine I, Urihnier C, Sikstrom B, KoskelaI Lehtinen M,c al. Seropositivities to huiiianpapillomavirus types16 18. o r 33 capsids and toC l i l m y d i a mi~/iaiiiafis re markers ofsexual behavior.J/i krf Dis 1 YY6;173:13Y4-8.
2000:77:3~+x.
IS .
18.
I ~ ~ x ; i 7 8 : 3 6 5 - 7 3 .
21.
22.
23.
24.
25.
26.
27.
28.
Andersson-Ellstroni A , Dillner J, Hagniar B, SchillerJ,Sapp M. Forssman L,ef al. Comparison ofdevelopment o f serum antibodiesto HPV16 andHI’V33 and acquisition of cervical H PV D N Aamong sexually experienced and virginal young girls.A longitudinal coh ort study.Sex 7?aTinrmi Dis
Anttila T, SaikkuP, Koskela P, Bloigu A. Dillner J.,lkaheinio I ef al Semtypes ofClilamydia rrarhoniarisand risk for developmentof cervical squamous cellcarcinoma.J A M A 2001;285:47-51.Bleeker MC, Hogewon ing CJ,VanDen Bru le AJ.Voorhorst FJ.Van A ndel R E, Risse Ek.er al Penilelesions and human papillomavirus in male sexualpartners of wom en with cervical intraepithelialncoplasia.J An] Acad Demiafo/2002;47 :35 1-7.Caste l lsayeX. osch FX, MunozN, Meijer CJ. ShahKV, de SanjoseS et al Male circumcision, penilehu man papillomavirus infection, and cervical cancerin female patients.N Engl j Med 2002;346:1105-12.Ylitalo N,Sorensen P, JoseGson A, Frisch M , SparenP,Ponten J.er a / Smoking and oral contraceptives asrisk factors for cervical carcinomain sitir. I i i r J CancerIY99;81:35745.Kjellberg L. Hallmans G.Ahren A M, JohanssonRBergman FWadellG ef al. Smoking, diet, pregnancy
and oral contraceptive useas
risk factors for cervicalintrd-epithelial neo plasia in relatio nto humanpapilloniavirur infection.BrJ Cancer 2000;82:1332-8.Szarewski A, Jarvis MJ, SasieniP Anderson M.Edwards R. Steele SJ,el al. Effect of smokingcessation on cervical lesion size.Lnncef1 YY6;347:Y4 1-3.LaVecchia C. Decarli A, FasoliM. Parauini F,Franceschi S Gentile A.el al. Dietary vitamin A andthe risk o f intraepithelial and invasive cervical
1 ~ ~ 6 ; 2 3 : 2 3 4 - n .
neoplasia. Cyiiecol OIKOI 988:30187-95.29. Meyskens FL Jr, Surwit E, Moon TE. Childers JM ,
Davis JR . Do rrRT, cf al Enhancement of regressionof cervical intraepithelial neoplasiaI I (moderatedysplasia) with topically applied all-trans-retinoic ac ida randomized trial.j Narl Catrccr h i s f lYY4;86:53Y-43.
30. Childers JM, Ch u J.Voigc LF, Feigl P.Tamimi HK .Franklin EW,ef al Chemoprevention of cervicalcancer with folic acid a phase111 SouthwestOncology Grou p Intergroup study.Caimr EpideiniolBiotnarken REV 995;4:155-Y.
31. Kols A, Sherris J.HPV Vocciiies: Promise and Cliallerip.Program for Appropriate Technology in Health:Seattle. Washington; 20 00.[www.path.org/files/jsrpl37 10. pdfl.
Further inform ation isavailable from the followingonline resources
A. Du gan -Ke en ME Brown MD, Stacey SN. Stern PL.Papillomaviurs vaccines.Fmnf Biaxi IY98;3:D11Y2-2011. [www.bioscience.org/l9Y8/v3/d/d u g g a d d l208.htniI.HPV 2000.Abstractson vaccine developm ent andtrials. In: Abstracts from 18th InternationalPapillomavirus Con fere nce : July 23-28; Barcel ona,Spain. 2000. [www.hpv20 00.com/topic.asp?desc=Vaccines%2ODevelopment??2Oand%2OTrials]
Cuzick J. Sasieni P, Davies P,Adams J. NormandC,Frater A,ef a1.A systematic review o f the role ofhuman papillomavirus testing within a cervicalscreening programme.Healfli Eclinol Assess1999;3.I-196. [www.hta.nhsweb.nhs.uk/fullmono/mon 314.pdfl.
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