Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma

Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2·5, which does not permit commercial exploitationBackground: Human papillomaviruses (HPVs) are sexually transmitted human carcinogens that may play a role in the oncogenesis of penile cancer. Objectives: To investigate the role of HPV infection and expression of the tumour suppressor protein p16INK4A in the pathogenesis of penile cancer. Methods: By means of polymerase chain reaction amplification and reverse hybridization line probe assay to detect HPV infection, and immunohistochemical staining for p16INK4A and Ki67, we analysed 26 penile squamous cell carcinomas (SCCs) and 20 independent penile lichen sclerosus (LS) lesions from 46 patients. Results: HPV DNA was found in 54% of penile SCCs and 33% of penile LS cases in single and multiple infections. High-risk HPV 16 was the predominant HPV type detected. No relationship between Ki67 expression and HPV infection was observed. Strong immunostaining for p16INK4A correlated with HPV 16/18 infection in both penile LS and penile SCC. In our penile SCC series the cancer margins were also associated with penile LS in 13 of 26 lesions, and HPV was detected in seven of the 13 SCC cases associated with LS and in six of the 11 SCC lesions not involving LS. Conclusions: Our study shows a high prevalence of HPV 16 and p16INK4A expression in penile lesions, consistent with an active role for HPV in interfering with the retinoblastoma pathway. High-risk HPV infection could be involved in the tumorigenic process in 50% of penile cancers, and the use of prophylactic HPV vaccines has the potential to prevent these cancers.Peer reviewedFinal Published versio

The Strong Protective Effect of Circumcision against Cancer of the Penis

Male circumcision protects against cancer of the penis, the invasive form of which is a devastating disease confined almost exclusively to uncircumcised men. Major etiological factors are phimosis, balanitis, and high-risk types of human papillomavirus (HPV), which are more prevalent in the glans penis and coronal sulcus covered by the foreskin, as well as on the penile shaft, of uncircumcised men. Circumcised men clear HPV infections more quickly. Phimosis (a constricted foreskin opening impeding the passage of urine) is confined to uncircumcised men, in whom balanitis (affecting 10%) is more common than in circumcised men. Each is strongly associated with risk of penile cancer. These findings have led to calls for promotion of male circumcision, especially in infancy, to help reduce the global burden of penile cancer. Even more relevant globally is protection from cervical cancer, which is 10-times more common, being much higher in women with uncircumcised male partners. Male circumcision also provides indirect protection against various other infections in women, along with direct protection for men from a number of genital tract infections, including HIV. Given that adverse consequences of medical male circumcision, especially when performed in infancy, are rare, this simple prophylactic procedure should be promoted

Risk of serious skin disorders among users of oral antifungals: a population-based study

BACKGROUND: Serious skin disorders have been associated with the use of oral antifungals in a number of case reports and series of cases. However the incidence of these disorders remains unknown. METHODS: We estimated the risk of serious skin disorders in a cohort of users of oral antifungals identified in the general population of the General Practice Research Database in the UK. The cohort included 61,858 patients, 20 to 79 years old, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. RESULTS: The background rate of serious cutaneous adverse reactions (the one corresponding to non use of oral antifungals) was 3.9 per 10,000 person-years (95% CI 2.9–5.2). Incidence rates for current use were 15.4 per 10,000 person-years (1.9–55.7) for itraconazole, 11.1 (3.0–28.5) for terbinafine, 10.4 (1.3–37.5) for fluconazole, and 4.6 (0.1–25.8) for griseofulvin. Itraconazole was the antifungal associated with the highest relative risk, 3.9 (0.5–15.0), when compared to the risk among non users, followed by terbinafine and fluconazole, with relative risks of 2.8 (0.7–7.8) and 2.6 (0.3–10.1), respectively. CONCLUSIONS: We conclude that cutaneous disorders associated with the use of oral antifungals in this study were all of mild severity and that the risk associated with the use of oral antifungals was slightly higher than the risk in non-users. The safety profile of terbinafine regarding cutaneous disorders is similar to other antifungals and in the very low range of risks associated with other drugs

Adult male circumcision to prevent HIV?

Summary: While the HIV pandemic persists, and randomized clinical trials to evaluate the effectiveness of male circumcision as an HIV prevention measure are underway with initial results being released, there is still much debate on the implications of these studies as well as on the feasibility of such a measure. This paper summarizes and discusses the main findings of studies of the evidence underlying adult male circumcision to prevent HIV, explores its feasibility and the implication for policy and future research. While the existing biological and epidemiological evidence suggest potential reduction of the risk of HIV acquisition in circumcised men, additional evidence from randomized trials are needed to confirm this. Even if the findings are confirmed, the practical aspects of implementing adult circumcision would have to be carefully considered. The feasibility of such an intervention, particularly with respect to its cost-effectiveness, safety and acceptability, is still to be demonstrated

Stroke risk and NSAIDs: A systematic review of observational studies

Aims: To perform a quantitative systematic review of observational studies on the risk of stroke associated with the use of individual NSAIDs. Methods and results: Searches were conducted using the Medline database within PubMed (1990-2008). Observational cohort or case-control studies were eligible if reported on the risk of cardiovascular events associated with individual NSAIDs versus the nonuse of NSAIDs. We found 3193 articles, in which 75 were eligible for review and abstraction. Of the 75 articles, 6 reported relative risk (RR) of stroke. Data were abstracted into a database using a standardized entry form. Two authors assessed study quality, and discrepancies were resolved by consensus. The pooled RR of all subtypes of incident stroke was increased with the current use of rofecoxib (RR=1.64, 95% CI=1.15-2.33) and diclofenac (RR=1.27, 95% CI=1.08-1.48). The pooled estimates for naproxen, ibuprofen, and celecoxib were close to unity. The risk of ischemic stroke was also increased with rofecoxib (RR=1.82, 95% CI=1.09-3.04) and diclofenac (RR=1.20, 95% CI=0.99-1.45). Data were inadequate to estimate the pooled RR by dose and duration, for other individual NSAIDs or nonischemic stroke subtypes. Conclusion: This meta-analysis supports an increased risk of ischemic stroke with the current use of rofecoxib and diclofenac. Additional studies are required to evaluate most individual NSAIDS, the effect of dose and duration, and the subtypes of stroke

Effectiveness of a real-life program (DIAfit) to promote physical activity in patients with type 2 diabetes: a pragmatic cluster randomized clinical trial.

INTRODUCTION The aim of this study was to evaluate the effectiveness of a real-life clinical physical activity program (DIAfit) on improving physical fitness, body composition, and cardiometabolic health in an unselected population with type 2 diabetes mellitus, and to compare the effects of two variants a different exercise frequencies on the same outcomes. RESEARCH DESIGN AND METHODS This was a cluster randomized-controlled assessor-blind trial conducted in 11 clinical centres in Switzerland. All participants in the clinical program with type 2 diabetes were eligible and were randomized to either standard (3 sessions/week for 12 weeks) or alternative (1 session/week for the first four weeks, then 2 sessions/week for the rest of 16 weeks) physical activity program each consisting of 36 sessions of combined aerobic and resistance exercise. Allocation was concealed by a central office unrelated to the study. The primary outcome was aerobic fitness. Secondary outcome measures included: body composition, BMI, HbA1c, muscle strength, walking speed, balance, flexibility, blood pressure, lipid profile. RESULTS All 185 patients with type 2 diabetes (mean age 59.7 +-10.2 years, 48% women) agreed to participate and were randomized in two groups: a standard group (n=88) and an alternative group (n=97)). There was an 11% increase in aerobic fitness after the program (12.5 Watts; 95% CI 6.76 to 18.25; p<0.001). Significant improvements in physical fitness, body composition, and cardiometabolic parameters were observed at the end of the DIAfit program (improvements between 2-29%) except for lean body mass, triglycerides and cholesterol. No differences were observed between both programs, except for a larger weight reduction of -0.97kg (95% CI -0.04 to -1.91; p=0.04) in the standard program. CONCLUSIONS Both frequency variants of the nation-wide DIAfit program had beneficial effects on physical fitness, HbA1c, body composition, and blood pressure in type 2 diabetes patients and differences were negligible. CLINICAL TRIAL REGISTRATION clinicaltrials.gov, identifier NCT01289587

Smoking and passive smoking in cervical cancer risk: pooled analysis of couples from the IARC multicentric case-control studies.

BACKGROUND: The independent role of tobacco smoking in invasive cervical cancer (ICC) has been established. We evaluated the potential impact of passive smoking (PS). METHODS: A pooled analysis of 1,919 couples enrolled in one of seven case-control studies involving cervical carcinoma in situ (CIS) or ICC was investigated. Information on smoking and sexual behavior was collected from interviews. Specimens were taken from the cervix and penis for human papillomavirus (HPV) DNA testing. Three PS risk models were constructed with all couples, couples with monogamous women, and couples with lifetime nonsmoking monogamous women. For the third model, the analysis considered potential misclassification of smoking status and was restricted to the risk period for which the woman was exposed to both HPV, a necessary cause of ICC, and PS. Multivariable unconditional logistic regression was used to estimate associations between CIS or ICC and PS. RESULTS: An increased risk was found among couples with both ever smoking men and women (OR = 2.26; 95% CI: 1.40-3.64). No statistically increased risk of CIS was found with PS in the models analyzed. Similar significant increased risks of ICC with PS was found among all couples (OR = 1.57; 95% CI: 1.15-2.15) and couples with monogamous women (OR = 1.55; 95% CI: 1.07-2.23) but not among lifetime nonsmoking monogamous women married to ever smoking men. CONCLUSION: PS could not be detected as an independent risk factor of ICC in the absence of active smoking. IMPACT: The combined effects of exposure to active and PS suggest its potential adverse role in cervical carcinogenesis

Urban–rural differences of gynaecological malignancies in Egypt (1999–2002)

Please cite this paper as: Dey S, Hablas A, Seifeldin I, Ismail K, Ramadan M, El-Hamzawy H, Wilson M, Banerjee M, Boffetta P, Harford J, Merajver S, Soliman A. Urban–rural differences of gynaecological malignancies in Egypt (1999–2002). BJOG 2010;117:348–355.In previous studies, we have shown a three to four times higher urban incidence of breast cancer and estrogen receptor-positive breast cancers in the Gharbiah Province of Egypt. We investigated the urban–rural incidence differences of gynaecologic malignancies (uterine, ovarian and cervical cancers) to explore if they show the same trend that we found for breast cancer.Cancer registry-based incidence comparison.Gharbiah population-based cancer registry (GPCR), Tanta, Egypt.All patients with uterine, ovarian and cervical cancer in GPCR from 1999 to 2002.We calculated uterine, ovarian and cervical cancer incidence from 1999 to 2002. For each of the three cancers, we calculated the overall and age-specific rates for the province as a whole, and by urban–rural status, as well as for the eight districts of the province.Incidence of all three cancer sites was higher in urban than in rural areas. Uterine cancer showed the highest urban–rural incidence rate ratio (IRR = 6.07, 95% CI = 4.17, 8.85). Uterine cancer also showed the highest urban incidence in the oldest age group (70+ age category, IRR = 14.39, 95% CI = 4.24, 48.87) and in developed districts (Tanta, IRR = 4.14, 95% CI = 0.41, 42.04). Incidence rates by groups of cancer sites showed an increasing gradient of urban incidence for cancers related to hormonal aetiology, mainly of the breast and uterus (IRR = 4.96, 95% CI = 2.86, 8.61).The higher urban incidence of uterine cancer, coupled with our previous findings of higher incidence of breast cancer and estrogen receptor positive breast cancer in urban areas in this region, may be suggestive of possible higher exposure to environmental estrogenic compounds, such as xenoestrogens, in urban areas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78726/1/j.1471-0528.2009.02447.x.pd

The age‐specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: Implications for screen‐and‐treat strategies

Cervical screening for carcinogenic human papillomavirus (HPV) infection is being considered for low‐income countries. Effectiveness requires targeted screening in older women in whom prevalent infections are more likely to be persistent and predictive of precancer. Some studies in West Africa have found unusually high HPV prevalences across all adult ages, which may reduce the positive predictive value (PPV) of HPV‐based screening, if positivity in older women does not sufficiently predict elevated risk. We conducted a population‐based study in rural Nigeria to identify HPV prevalence and associated cervical abnormalities. Using stratified random sampling, we enrolled women age 15+. Nonvirgins had a cervical exam including liquid‐based cytology and PCR HPV DNA testing from residual cytology specimens. Two‐thirds of invited women participated, and 14.7% had detectable carcinogenic HPV, a proportion that did not decline with age ( p ‐trend = 0.36) and showed slight peaks in the 15–29 and 60–69 age groups. Among women of the age typically considered for screen‐and‐treat programs (30–49 years), 12.8% were HPV positive, and the PPV for high‐grade or worse cytology was 16.4%. Comparatively, women age < 30 were more likely to be HPV positive (18.9%, p = 0.03) with a lower PPV (4.2% p = 0.05). Among women age 50+ (typically excluded from screening in resource‐poor settings because inexpensive treatment is not available), HPV positivity was 14.2% with a PPV of 13.9%. In Irun and similar settings where HPV does not decline with age, HPV‐based screen‐and‐treat programs might be feasible for mid‐adult women because prevalence is sufficiently low and positivity predicts elevated risk of more easily treated precancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90127/1/26211_ftp.pd

The Perceptions on Male Circumcision as a Preventive Measure Against HIV Infection and Considerations in Scaling up of the Services: A Qualitative Study Among Police Officers in Dar es Salaam, Tanzania.

\ud In recent randomized controlled trials, male circumcision has been proven to complement the available biomedical interventions in decreasing HIV transmission from infected women to uninfected men. Consequently, Tanzania is striving to scale-up safe medical male circumcision to reduce HIV transmission. However, there is a need to investigate the perceptions of male circumcision in Tanzania using specific populations. The purpose of the present study was to assess the perceptions of male circumcision in a cohort of police officers that also served as a source of volunteers for a phase I/II HIV vaccine (HIVIS-03) trial in Dar es Salaam, Tanzania. In-depth interviews with 24 men and 10 women were conducted. Content analysis informed by the socio-ecological model was used to analyze the data. Informants perceived male circumcision as a health-promoting practice that may prevent HIV transmission and other sexually transmitted infections. They reported male circumcision promotes sexual pleasure, confidence and hygiene or sexual cleanliness. They added that it is a religious ritual and a cultural practice that enhances the recognition of manhood in the community. However, informants were concerned about the cost involved in male circumcision and cleanliness of instruments used in medical and traditional male circumcision. They also expressed confusion about the shame of undergoing circumcision at an advanced age and pain that could emanate after circumcision. The participants advocated for health policies that promote medical male circumcision at childhood, specifically along with the vaccination program. The perceived benefit of male circumcision as a preventive strategy to HIV and other sexually transmitted infections is important. However, there is a need to ensure that male circumcision is conducted under hygienic conditions. Integrating male circumcision service in the routine childhood vaccination program may increase its coverage at early childhood. The findings from this investigation provide contextual understanding that may assist in scaling-up male circumcision in Tanzania.\u