Human Papillomavirus Infection in Penile Cancer: Multidimensional Mechanisms and Vaccine Strategies.

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms of virus-host genome integration patterns (the disrupted regions in the HPV and PC genome), genetic alterations, and epigenetic regulation (methylation and microRNA modification) occurring in HPV and PC DNA, as well as tumor immune microenvironment reprogramming. In addition, the potential of HPV vaccination strategies for PC prevention and treatment is discussed. Understanding of the HPV-related multidimensional mechanisms and the application of HPV vaccines will promote rational and novel management of PC.

Human papillomavirus vaccination and prevention of intraepithelial neoplasia and penile cancer: review article.

PURPOSE OF REVIEW: The objective of the current article is to promote a literature revision of the relationship between the prevention of intraepithelial neoplasms (PeIN) and invasive penile cancer, and human papillomavirus (HPV) vaccination, aiming to enumerate the pros and cons of immunization. RECENT FINDINGS: The immunization against the HPV is sufficiently safe and many countries have incorporated the vaccine to their immunization calendar. Compared with men, the sampling size and the evidence quality of scientific researches among the female population are more robust. Some randomized and nonrandomized studies suggest that vaccination reduces the incidence of genital warts and no PeIN and penile cancer cases were developed in the vaccinal group. However, 70% of patients can evolve with the neoplasia despite having been immunized and even among HPV infected patients, only 1% will develop cancer. SUMMARY: The studies about vaccination against HPV and prevention on penile cancer are conflicting and the main academic urology societies still have not incorporated vaccination of men in their guidelines. Future studies are necessary to confirm the efficiency and cost-benefit of the vaccine in men to prevent intraepithelial neoplasms and invasive penile cancer.

Systematic review and evidence synthesis of non-cervical human papillomavirus-related disease health system costs and quality of life estimates.

BACKGROUND: Many economic evaluations of human papillomavirus vaccination should ideally consider multiple disease outcomes, including anogenital warts, respiratory papillomatosis and non-cervical cancers (eg, anal, oropharyngeal, penile, vulvar and vaginal cancers). However, published economic evaluations largely relied on estimates from single studies or informal rapid literature reviews. METHODS: We conducted a systematic review of articles up to June 2016 to identify costs and utility estimates admissible for an economic evaluation from a single-payer healthcare provider's perspective. Meta-analyses were performed for studies that used same utility elicitation tools for similar diseases. Costs were adjusted to 2016/2017 US$. RESULTS: Sixty-one papers (35 costs; 24 utilities; 2 costs and utilities) were selected from 10 742 initial records. Cost per case ranges were US$124-US$883 (anogenital warts), US$6912-US$52 579 (head and neck cancers), US$12 936-US$51 571 (anal cancer), US$17 524-34 258 (vaginal cancer), US$14 686-US$28 502 (vulvar cancer) and US$9975-US$27 629 (penile cancer). The total cost for 14 adult patients with recurrent respiratory papillomatosis was US$137 601 (one paper).Utility per warts episode ranged from 0.651 to 1 (12 papers, various utility elicitation methods), with pooled mean EQ-5D and EQ-VAS of 0.86 (95% CI 0.85 to 0.87) and 0.74 (95% CI 0.74 to 0.75), respectively. Fifteen papers reported utilities in head and neck cancers with range 0.29 (95% CI 0.0 to 0.76) to 0.94 (95% CI 0.3 to 1.0). Mean utility reported ranged from 0.5 (95% CI 0.4 to 0.61) to 0.65 (95% CI 0.45 to 0.75) (anal cancer), 0.59 (95% CI 0.54 to 0.64) (vaginal cancer), 0.65 (95% CI 0.60 to 0.70) (vulvar cancer) and 0.79 (95% CI 0.74 to 0.84) (penile cancer). CONCLUSIONS: Differences in values reported from each paper reflect variations in cancer site, disease stages, study population, treatment modality/setting and utility elicitation methods used. As patient management changes over time, corresponding effects on both costs and utility need to be considered to ensure health economic assumptions are up-to-date and closely reflect the case mix of patients.

Detection of human papillomavirus in urine among heterosexual men in relation to location of genital warts and circumcision status.

OBJECTIVE: Human papillomavirus (HPV) surveillance is important to monitor the effectiveness of national HPV vaccination programmes. Positivity of HPV in urine in men varies with different sampling methods. We aimed to determine the positivity for detection of HPV-6/11 in urine samples among men in relation to the position of genital warts and circumcision status. METHOD: We analysed stored chlamydia-positive urine specimens in young heterosexual men aged less than 25 years attending Melbourne Sexual Health Centre, Australia, between 2004 and 2015, for HPV genotypes. Positivity of HPV-6/11 and high-risk genotypes were stratified according to the position of genital warts and circumcision status. Positivity of HPV-6/11 was calculated using diagnosis of warts as the gold standard. Warts were classified as proximal penile warts from suprapubic area to midshaft of penis, and distal penile warts from distal shaft of penis to meatus. RESULTS: Of the 934 specimens, 253 (27.1%) men were positive for any HPV and 82 men (8.8%) had genital warts. The ORs of HPV-6/11 detection in urine were 4.63 (95% CI: 1.68 to 12.78) and 40.20 (95% CI: 19.78 to 81.70) times higher among men who had proximal penile warts and distal penile warts, respectively, compared with men who did not have genital warts. Circumcised men were less likely to have high-risk HPV (OR 0.31; 95% CI: 0.14 to 0.65) than uncircumcised men. Uncircumcised men were more likely to have distal penile warts than circumcised men (OR 8.22; 95% CI: 1.34 to 337.46). CONCLUSION: Positivity of HPV-6/11 in urine increases greatly in men with distal penile warts. Circumcised men are less likely to have distal penile warts, any HPV or high-risk HPV detected. Urine is likely to be an alternative sampling method for HPV-6/11 surveillance programme in men in countries with low circumcision rates.

Epidemiological dynamic modeling of human papillomavirus-related diseases to assess vaccination strategies in Argentina.

Our objective was to develop and test a dynamic simulation model of human papillomavirus (HPV)-related diseases to assess rational vaccination strategies in Argentina. A dynamic stochastic transmission model for hetero- and homosexual transmission of HPV oncogenic and low-risk oncogenic types among females and males was developed. The model included HPV transmission and vaccination, the natural history of HPV-related diseases, disease outcomes, and cervical cancer screening. Considering all cervical cancers, covered or not by the current quadrivalent vaccine, the existing coverage rate would lead to 60% reduction in the global incidence of cervical cancer at 25 years, and to 79% at 50 years. Isolated current female vaccination without a screening program would need around 100 years to eliminate cervical cancer from the local population. Current coverage rate would lead to 59% reduction of vulvar cancer, 76% of vaginal cancer, 85% of anal cancer, and 87% of oropharyngeal cancer, estimated over a 25-year time prospect. Female HPV vaccination within the context of current cervical cancer screening should reach a minimum long-term mean coverage of 60% of girls, receiving at least a two-dose vaccine schedule, to significantly reduce or virtually eliminate cervical cancer at 50 years. Including vaccination to boys to improve herd immunity did not influence the incidence of cervical cancer over time, as long as female coverage did not fall below 50%. Regarding vulvar, vaginal, anal, penile, and some oropharyngeal cancers, current girls-only based vaccination could virtually eliminate these cancer types after 35-40 years, both in women and men.

Estimating the cost-effectiveness profile of a universal vaccination programme with a nine-valent HPV vaccine in Austria.

BACKGROUND: HPV is a major cancer-causing factor in both sexes in the cervix, vulva, vagina, anus, penis, oropharynx as well as the causal factor in other diseases such as genital warts and recurrent respiratory papillomatis. In the context of the arrival of a nonavalent HPV vaccine (6/11/16/18/31/33/45/52/58), this analysis aims to estimate the public health impact and the incremental cost-effectiveness of a universal (girls and boys) vaccination program with a nonavalent HPV vaccine as compared to the current universal vaccination program with a quadrivalent HPV vaccine (6/11/16/18), in Austria. METHOD: A dynamic transmission model including a wide range of health and cost outcomes related to cervical, anal, vulvar, vaginal diseases and genital warts was calibrated to Austrian epidemiological data. The clinical impact due to the 5 new types was included for cervical and anal diseases outcomes only. In the base case, a two-dose schedule, lifelong vaccine type-specific protection and a vaccination coverage rate of 60% and 40% for girls and boys respectively for the 9-year old cohorts were assumed. A cost-effectiveness threshold of €30,000/QALY-gained was considered. RESULTS: Universal vaccination with the nonavalent vaccine was shown to reduce the incidence of HPV16/18/31/33/45/52/58 -related cervical cancer by 92%, the related CIN2/3 cases by 96% and anal cancer by 83% and 76% respectively in females and males after 100 years, relative to 75%, 76%, 80% and 74% with the quadrivalent vaccine, respectively. Furthermore, the nonavalent vaccine was projected to prevent an additional 14,893 cases of CIN2/3 and 2544 cases of cervical cancer, over 100 years. Depending on the vaccine price, the strategy was shown to be from cost-saving to cost-effective. CONCLUSION: The present evaluation showed that vaccinating 60% of girls and 40% of boys aged 9 in Austria with a 9-valent vaccine will substantially reduce the incidence of cervical cancer, CIN and anal cancer compared to the existing strategy. The vaccination strategies performed with the 9-valent vaccine in the current study were all found to be cost-effective compared to the current quadrivalent vaccination strategy by considering a cost-effectiveness threshold of 30,000€/QALY gained.

A Contemporary Review of HPV and Penile Cancer.

Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women.

[PAPILLOMAVIRUS INFECTION: PRINCIPLE CHARACTERISTICS, CLINICAL MANIFESTATIONS, VACCINE PROPHYLAXIS].

Papillomaviruses are a large and diverse group of viruses. It includes approximately 200 fully described types that have been detected in humans. Human papilloma viruses (HPV) are etiologic agents during various, benign and malignant lesions of mucous membrane and skin epithelium. Very importantly, persistent HPV infection of certain types is a leading cause of carcinoma of uterine cervix, penis, vulva; vagina, anal canal and fauces (including tongue base and tonsils). HPV infection prophylaxis is the best means to control HPV-conditioned diseases, and vaccination, as had been demonstrated, --the most effective method of its prophylaxis. In this paper principle characteristics and clinical manifestations of papillomavirus infection, as well as effectiveness of vaccination against HPV are examined.

The burden of HPV-associated anogenital cancers.

The epidemiology of anogenital cancers is under going substantial change. Cervical cancer remains a major public health concern, particular in resource-limited settings. Cancers of the anus, penis, vagina and vulva are relatively uncommon cancers, but may be increasing in incidence. The change in occurrence of anogenital cancers may be due to increasing HPV transmission secondary to changes in sexual behaviour. Screening programmes and the HPV vaccine offer optimism that anogenital cancers can be prevented. This article reviews the epidemiology of anogenital cancers with a focus on Scottish data.

[Long-term benefit of male circumcision to the reduction of urinary tract infections and genitourinary cancers in China].

Increasingly accumulated results from randomized controlled trials and other clinical studies have demonstrated that male circumcision reduces the risks of acquisition and transmission of HIV, HPV, HSV-2, and other sexually transmitted infections, and thus has a potential role in preventing cervical cancer, penile cancer and prostate cancer. The prevalence of male circumcision in China is currently less than 5%. The clinical evaluation studies and randomized controlled trials of the Shang Ring device showed excellent safety profiles, extremely high acceptability, and satisfaction among the participants and service providers in Africa and China. Given the recent recommendations by the World Health Organization and the Joint United Nations Program on HIV/AIDS (UNAIDS), voluntary medical male circumcision should be promoted in China at the national level as an important alternative intervention to reduce reproductive tract infections and prevent both males and females from reproductive tract cancers. More emphasis is required on the studies of the long-term health benefits of male circumcision in uro-andrology.

[Anticipated efficacy of HPV vaccination in prophylaxis against nongenital cancers]. / Predpokládaná úcinnost HPV vakcinace v profylaxi nongenitálních karcinomu

BACKGROUND: There is a considerable number of studies on the efficacy HPV (human papillomavirus) vaccination against different cancers but relevant information is scattered in diverse journals. This paper is a review summarizing current knowledge of the potential of HPV vaccination against all HPV related cancers. AIM: HPV infection is probably the most frequent sexually transmitted disease. At least 13 HPV genotypes are classified as carcinogenic or probably carcinogenic in respect to cervical cancer. Almost 100% of cervical cancers are linked to HPV infection. HPV 16 and HPV 18 are the most frequently involved genotypes and account together for approximately 70% of cervical cancer in the world. Persistent high risk HPV infection is responsible for a significant proportion of vulvar, vaginal, anal and penile carcinomas. The virus has also been implicated in oncogenesis of head and neck cancers, including oropharyngeal cancers. HPV infection can play an important role in cancerogenesis of lung, esophagus, breast, and colon and rectum. On the contrary, published results indicate that HPV infection is not associated with prostate oncogenesis. Strong predominance of HPV 16 has been reported for all HPV associated cancer sites. Generally, it is estimated that approximately 5.2% of all cancers are associated with oncogenic HPV infection. Currently, there are two vaccines on the market; quadrivalent Silgard® (Gardasil®) and bivalent CervarixTM. Large trials for both vaccines have shown efficacy against HPV related infection and disease. Efficacy has been very high in HPV naive subjects to vaccine related types. While HPV vaccination is currently approved for the prevention of cervical cancer, it also has the potential in the prevention of all HPV associated malignancies. The Czech republic belongs to countries that cover HPV vaccination of girls at the age of 13- 14 years by general health insurance. Overall impact of this vaccination remains to be evaluated. The new issues of the role of HPV in oncogenesis, as well as the potential effect of HPV vaccination against HPV related nongenital cancers are discussed. CONCLUSION: Approximately 5.2% of all human cancers are associated with oncogenic human papillomavirus infection. HPV vaccination against the most risky HPV oncotypes may cause a significant reduction of these cancers mainly in the HPV naive population.

Estimating the clinical benefits of vaccinating boys and girls against HPV-related diseases in Europe.

BACKGROUND: HPV is related to a number of cancer types, causing a considerable burden in both genders in Europe. Female vaccination programs can substantially reduce the incidence of HPV-related diseases in women and, to some extent, men through herd immunity. The objective was to estimate the incremental benefit of vaccinating boys and girls using the quadrivalent HPV vaccine in Europe versus girls-only vaccination. Incremental benefits in terms of reduction in the incidence of HPV 6, 11, 16 and 18-related diseases (including cervical, vaginal, vulvar, anal, penile, and head and neck carcinomas and genital warts) were assessed. METHODS: The analysis was performed using a model constructed in Microsoft(®)Excel, based on a previously-published dynamic transmission model of HPV vaccination and published European epidemiological data on incidence of HPV-related diseases. The incremental benefits of vaccinating 12-year old girls and boys versus girls-only vaccination was assessed (70% vaccine coverage were assumed for both). Sensitivity analyses around vaccine coverage and duration of protection were performed. RESULTS: Compared with screening alone, girls-only vaccination led to 84% reduction in HPV 16/18-related carcinomas in females and a 61% reduction in males. Vaccination of girls and boys led to a 90% reduction in HPV 16/18-related carcinomas in females and 86% reduction in males versus screening alone. Relative to a girls-only program, vaccination of girls and boys led to a reduction in female and male HPV-related carcinomas of 40% and 65%, respectively and a reduction in the incidence of HPV 6/11-related genital warts of 58% for females and 71% for males versus girls-only vaccination. CONCLUSIONS: In Europe, the vaccination of 12-year old boys and girls against HPV 6, 11, 16 and 18 would be associated with substantial additional clinical benefits in terms of reduced incidence of HPV-related genital warts and carcinomas versus girls-only vaccination. The incremental benefits of adding boys vaccination are highly dependent on coverage in girls. Therefore, further analyses should be performed taking into account the country-specific situation. In addition to clinical benefits, substantial economic benefits are also anticipated and warrant further investigation as do the social and ethical implications of including boys in vaccination programs.

Out of step: fatal flaws in the latest AAP policy report on neonatal circumcision.

The American Academy of Pediatrics recently released a policy statement and technical report on circumcision, in both of which the organisation suggests that the health benefits conferred by the surgical removal of the foreskin in infancy definitively outweigh the risks and complications associated with the procedure. While these new documents do not positively recommend neonatal circumcision, they do paradoxically conclude that its purported benefits 'justify access to this procedure for families who choose it,' claiming that whenever and for whatever reason it is performed, it should be covered by government health insurance. The policy statement and technical report suffer from several troubling deficiencies, ultimately undermining their credibility. These deficiencies include the exclusion of important topics and discussions, an incomplete and apparently partisan excursion through the medical literature, improper analysis of the available information, poorly documented and often inaccurate presentation of relevant findings, and conclusions that are not supported by the evidence given.

Circumcision related to urinary tract infections, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer.

Male circumcision has been carried out as a prophylactic measure against future diseases, as well as a rite of passage due to religious practice and definite medical indication. The present review discusses the benefits of male circumcision on the prevention of urinary tract infections, and the importance of circumcision in congenital urinary system anomalies, such as vesicoureteral reflux. Additionally the present review examines the associations between circumcision and sexually transmitted infections, including human immunodeficiency virus, and the preventive effect of circumcision on penile cancer and cervical cancer of female partners.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease.

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ~600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

Quality of life valuations of HPV-associated cancer health states by the general population.

OBJECTIVES: To obtain health-related quality of life valuations (ie, utilities) for human papillomavirus (HPV)-related cancer health states of vulval, vaginal, penile, anal and oropharyngeal cancers for use in modelling cost-effectiveness of prophylactic HPV vaccination. METHODS: Written case descriptions of each HPV-associated cancer describing the 'average' patient surviving after the initial cancer diagnosis and treatment were developed in consultation with oncology clinicians. A general overview, standard gamble questionnaire for each health state and a quiz was conducted in 120 participants recruited from the general population. RESULTS: In the included population sample (n=99), the average age was 43 years (range = 18-70 years) with 54% men, 44% never married/43% married, 76% education beyond year 12 and 39% employed full-time. The utility values for the five health states were 0.57 (95% CI 0.52 to 0.62) for anal cancer, 0.58 (0.53 to 0.63) for oropharyngeal cancer, 0.59 (0.54 to 0.64) for vaginal cancer, 0.65 (0.60 to 0.70) for vulval cancer and 0.79 (0.74 to 0.84) for penile cancer. Participants demonstrated a very good understanding of the symptoms, diagnosis and treatment of these cancers with a mean score of 9 (SD=1.1) on a 10-item quiz. CONCLUSIONS: This study provides utility estimates for the specific HPV-related cancers of vulval, vaginal, penile, anal and oropharyngeal cancers valued by a general population sample using standard gamble. The results demonstrate considerable quality of life impact associated with surviving these cancers that will be important to incorporate into modelling cost-effectiveness of prophylactic HPV vaccination in different populations.