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Cervical Cancer a Global Problem

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Cervical Cancer a Global Problem Cervical Cancer The long road from discovery global eradication TRI, The University of Queensland Brisbane, Australia Cervical Cancer A global problem The global burden of HPV associated cancer – 330,000 deaths/year Source: Globocan 2008 : IARC and WHO : 2015 Cervical Cancer elimination The beginning Giornale per servire ai progressi della patologia e della terapeutica Domenico Antonio Rigoni-Stern(1842) Rigoni-Stern and Medical Statistics A Nineteenth-Century Approach to Cancer Research JOSEPH SCOTTO AND JOHN C. BAILAR, III Journal of the History of Medicine : January 1969 Giornale per servire ai progressi della patologia e della terapeutica (1842) Domenico Antonio Rigoni-Stern STATISTICAL DATA RELATIVE TO THE DISEASE OF CANCER WHICH SERVE AS THE “….why“TheBASIS FORincidence SOMEeven BRIEF isREMARKS breastof MADE uterine BY DR. cancer RIGONI -STERNcancer ONthe THE 23RD mostis OFnot “ cancersSEPTEMBER are AT THE more SUBSESSION frequent OF SURGERY in OF THEnuns FOURTH than CONGRESS in other OF ITALIAN womenfrequentincreasedSCIENTISTS at a ratio cancer through of about among the 5 to licentious 1.”nuns? Could it be “thetheirpractices frequency habits of of arewomen; the toocancers tight?however, of the Or, uterus the perhaps, isrisk is inverselythegreater long related -amongsustained, to thatwomen of bent the who cancersposition are excessivelyof theassumed breast” whilesensitive saying morally prayers and with nervously forearms irritable” resting on knees and compressing the breasts.” Rigoni-Stern and Medical Statistics A Nineteenth-Century Approach to Cancer Research JOSEPH SCOTTO AND JOHN C. BAILAR, III Journal of the History of Medicine : January 1969 A great step forward Georgios Papanikolaou Screening for cervical cancer First description in 1928 “Diagnosis of Uterine Cancer Georgios Nikolaou by the Vaginal Smear”(1943) Papanikolaou 1883-1962 Quinn M et al BMJ 1999; 318 904- 908 The swinging sixties Sexual activity and cervical cancer American Journal of Public Health Volume 57(5); 1967 May “Epidemiology of cancer of the cervix. 3 Sexual characteristics of a cervical cancer population” I D Rotkin https://www.ncbi.nlm.nih.gov/pmc/journals/259 A substudy of97 patients with cervical cancer and 97 matching controls: …..a considerable excess of patients with first coitus on the ground, compared to a heavy excess of controls with first coitus in a hotel or motel. The progressive 70’s : Is infection to blame ? • Cancer Res. 1974 May;34(5):1111-7. Epidemiological studies relating genital herpetic infection to cervical carcinoma “The high frequency of herpes simplex virus type 2 (HSV-2) antibodies in young women (21 years or younger) with cervical carcinoma in situ and in women with dysplasia or carcinoma in situ, matched for various sexual attributes to control women, provide support for a causal relation.” Harald Zur Hausen : the age of enlightenment Condylomata Acuminata and Human Genital Cancer, Cancer Res. 1976 Feb;36(2 pt 2):794. The condyloma agent has been entirely neglected thus far in all epidemiological and serological studies relating not only to cervical and penile, but also to vulvar and perianal, carcinomas. This is particularly unusual in view of the localization of genital warts, their mode of venereal transmission, the number of reports on malignant transition, and the presence of an agent belonging to a well- characterized group of oncogenic DNA viruses. Boshart, Michael, Lutz Gissman, Hans Ikenberg, Andreas Kleinheinz, Wolfram Scheurlen, and Harald zur Hausen. "A New Type of Papillomavirus DNA, Its Presence in Genital Cancer Biopsies and in Cell Lines Derived from Cervical Cancer." The EMBO Journal 3 (1984): 1151– 1157. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC557488 /pdf/emboj00309-0223 .pdf Transformation of cells by HPV Watts SL, Phelps WC, Ostrow RS, Zachow KR, Faras AJ (1984) Cellular transformation by human papillomavirus DNA in vitro. Science 225:634–636. Pirisi L, Yasumoto S, Feller M, Doniger J, DiPaolo JA (1987) Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol 61:1061–1066. Bedell MA, Jones KH, Laimins LA (1987) The E6–E7 region of human papillomavirus type 18 is sufficient for transformation of NIH 3T3 and rat-1 cells. J Virol 61:3635–3640. Dürst M, Dzarlieva-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L (1987) Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA. Oncogene 1:251–256. Kaur P, McDougall JK, Cone R (1989) Immortalization of primary human epithelial cells by cloned cervical carcinoma DNA containing human papillomavirus type 16 E6/E7 open reading frames. J Gen Virol 70:1261–1266. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421 Halbert CL, Demers GW, Galloway DA (1991) The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65:473–478. The beginning of the end Treating HPV infections : a challenge Preventing them is more sensible Papillomavirus vaccine development First learn the natural history Zur of the disease Hausen HPV 16 Cancer associated Human Papillomaviruses Fraction infected Residual infection (~1980) Months since onset of Sexual activity - High risk HPV infection is common - Two common (16,18) and several rarer types - >95% resolve spontaneously –median 1.5yrs - 2% progress to cancer over 15 years - Unexpectedly, detection of pre-cancer is possible 1- 2 years post infection Harriet Richardson, Gail Kelsall, Pierre Tellier, Helene Voyer, Michal Abrahamowicz, Alex Ferenczy, Francois Coutlee, and Eduardo L. Franco Cancer Epidemiology, Biomarkers & Prevention Vol. 12, 485–490, June 2003 Vaccines to prevent HPV infection Zur Hausen Jian Zhou Cancer associated Human Virus Like particles1 Papillomaviruses (~1990) (~1980) - L1 recombinant DNA -Some HPVs cause cancer - Self assembly to VLPs - Virus can’t be grown in the lab - VLPs highly immunogenic 1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991. VLP vaccine citations Virus Clinical Lesion 200 Atg Atg L1 L1 gene Eukaryotic Cell + 150Expression Vector Gene expression Expression Patenting enabled by: Vector 100 1)Eukaryotic Expression Gene cloning 2) 2nd ATG start site 3) DNA from infection Citations/year Virus Like particle purification 50 not cancer 0 1993 1998 2003 2008 2013 Year ALUM Clinical trial validation Vaccine Addition of adjuvant Expression systems with better yield Vaccines to prevent HPV infection Ed Scolnick Harald Zur Hausen Jian Zhou Kathrin Jansen Cancer associated Human Virus Like particles1 HPV vaccines Papillomaviruses (~1990) (~2005) (~1980) - L1 recombinant DNA -Conventional vaccines -Some HPVs cause cancer - Self assembly to VLPs - VLPs+ adJuvant - Virus can’t be grown in the lab - VLPs highly immunogenic - Neutralising Antibody - Protection > 5yrs - Safe 1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991. The vaccine needed many people and a hard end point to prove efficacy Vaccine Study Vaccine No of subjects End-points efficacy Vaccine Control % ( confidence limits) Koutsky 6/11/16/18 6087 6080 CIN 2/3 AIS 98 (86-100) Ault 6/11/16/18 10291 10292 CIN 2/3 AIS 99 (93-100) 2241 2258 CIN 2/3 AIS 100 (94-100) Garland 6/11/16/18 2261 2279 GW VIN VAIN 100 (94-100) 7811 7785 VIN2/3 VAIN 100 (72-100) Joura 6/11/16/18 2/3 CIN2,3 93 (89-98) Parvonen* 16/18 9319 9325 Adapted from J. A. Kahn and R. D. Caveat Burk. Papillomavirus vaccines in prevention of premalignancy perspective. Lancet 369 (9580):2135-2137, 2007. - in HPV naïve subjects, - disease caused by vaccine HPV types *: Phase III bivalent vaccine data from 25th IPV Malmo 2009 Nine steps to translate HPV research into practical outcomes • Define the problem – HPV and cancer Zur Hausen • Develop the science –recombinant VLPS Jian Zhou • Find commercial partners Merck/GSK • Scale up the manufacture Merck/GSK • Complete safety and efficacy trials Many groups • Educate the profession, govt, the public Ongoing • Confirm field efficacy • Improve the product – 9 valent vaccines, 2 dose regimens • Encourage deployment globally • Develop effective immunotherapy Genital warts have disappeared in young vaccinated women in Australia H.Ali, B.Donovan, H. Wand, T Read, D.Regan, A. Grulich, C Fairley, R. Guy, BMJ 2013;346:f2032 doi: 10.1136/bmj.f2032 Genital Warts have also disappeared in their unvaccinated male partners H.Ali, B.Donovan, H. Wand, T Read, D.Regan, A. Grulich, C Fairley, R. Guy, BMJ 2013;346:f2032 doi: 10.1136/bmj.f2032 HPV VLP vaccines are not therapeutic! We need something else for those already infected Immunised At 14 No exposure Good protection Immunised At 17 Prior exposure Poor protection Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. Dorota M Gertig, , Julia ML Brotherton, Alison C Budd, Kelly Drennan Genevieve Chappell and A Marion Saville BMC Medicine 2013, 11:227 doi:10.1186/1741-7015-11-227 ENABLING GLOBAL USE There is disparity between HPV vaccine programs and cervical cancer prevalence http://www.indexmundi.com/blog/wp-content/uploads/2013/05/HPV-vaccine-infographic.jpg Vaccine delivery logistics in Vanuatu: staffing, and a cold chain Vanuatu ->50 islands ~250,000 people ~25 doctors -91 parliamentarians! -1 vaccine fridge -0 reliable electricity
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