Decline in genital warts diagnoses among young women and young men since the introduction of the bivalent HPV (16/18) vaccination programme in England: an ecological analysis.

BACKGROUND: For several decades, diagnoses of genital warts at genitourinary medicine (GUM) clinics in England had been increasing. In 2008, a national human papillomavirus (HPV) vaccination programme was introduced using the bivalent vaccine (types 16 and 18 only). A decrease in genital warts was not anticipated. However, rates of genital warts in GUM clinics have declined significantly since the introduction of the vaccine. METHODS: Using data from GUM clinics across England, we analysed rates of genital warts by age, gender, sexual orientation and estimated vaccine coverage. RESULTS: The reduction in rates of genital warts diagnoses at GUM clinics between 2009 and 2014 was 30.6% among young women aged 15-19 years and 25.4% among same age heterosexual young men. Overall there was an association showing higher warts reduction with increasing vaccination coverage with the largest declines in warts diagnoses observed in young women aged 15 years (50.9%) with the highest vaccination coverage. No such declines were observed in men who have sex with men (MSM) of the same age. CONCLUSION: The results of these ecological analyses are strongly in keeping with the bivalent HPV vaccine providing modest protection against genital warts.

Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records.

OBJECTIVE: To compare time to diagnosis of the typically slow-growing Type I (low-grade serous, low-grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high-grade serous, high-grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC). DESIGN: Multicentre observational study. SETTING: Ten UK gynaecological oncology centres. POPULATION: Women diagnosed with primary EOC between 2006 and 2008. METHODS: Symptom data were collected before diagnosis using patient questionnaire and primary-care records. We estimated patient interval (first symptom to presentation) using questionnaire data and diagnostic interval (presentation to diagnosis) using primary-care records. We considered the impact of first symptom, referral and stage on intervals for Type I and Type II iEOC. MAIN OUTCOME MEASURES: Patient and diagnostic intervals. RESULTS: In all, 78% of 60 Type I and 21% of 134 Type II iEOC were early-stage. Intervals were comparable and independent of stage [e.g. median patient interval for Type I: early-stage 0.3 months (interquartile range 0.3-3.0) versus late-stage 0.3 months (interquartile range 0.3-4.5), P = 0.8]. Twenty-seven percent of women with Type I and Type II had diagnostic intervals of at least 9 months. First symptom (questionnaire) was also similar, except for the infrequent abnormal bleeding (Type I 15% versus Type II 4%, P = 0.01). More women with Type I disease (57% versus 41%, P = 0.04) had been referred for suspected gynaecological cancer. Median time from referral to diagnosis was 1.4 months for women with iEOC referred via a 2-week cancer referral to any specialty compared with 2.6 months (interquartile range 2.0-3.7) for women who were referred routinely to gynaecology. CONCLUSION: Overall, shorter diagnostic delays were seen when a cancer was suspected, even if the primary tumour site was not recognised to be ovarian. Despite differences in carcinogenesis and stage for Type I and Type II iEOC, time to diagnosis and symptoms were similar. Referral patterns were different, implying subtle symptom differences. If symptom-based interventions are to impact on ovarian cancer survival, it is likely to be through reduced volume rather than stage-shift. Further research on histological subtypes is needed. TWEETABLE ABSTRACT: No difference in time to diagnosis for Type I versus Type II invasive epithelial ovarian cancers.

Coverage of the English national human papillomavirus (HPV) immunisation programme among 12 to 17 year-old females by area-level deprivation score, England, 2008 to 2011.

The English national human papillomavirus (HPV) immunisation programme has offered vaccination to girls aged 12 years at the start of each school year since September 2008. A catch-up programme has offered vaccination to girls up to 18 years. Delivery is predominantly school-based, with some general practitioner (GP)-based immunisation. The relationship between HPV immunisation coverage and deprivation (index of multiple deprivation, IMD) was assessed by geographical area (N=151) for each school year offered the HPV vaccine between 2008 to 2011 using the Spearman's rank correlation coefficient, and compared to that for adequate cervical screening of women aged 25 to 49 years. Coverage at age 12 showed no significant association with IMD at the area-level (p=0.12). Within the catch-up years, there was some suggestion of higher deprivation being associated with lower coverage. This was not significant for girls offered immunisation under 16 years (in compulsory education) (p=0.09), but was more marked and statistically significant for older girls (p<0.0001). The proportion of women aged 25 to 49 years with an adequate cervical screen was negatively associated with deprivation (p<0.0001). School-based HPV immunisation delivery appears to be successfully reducing inequalities in cervical cancer control at area-level. However, the catch-up cohorts above the age of compulsory education may face increased inequality. Further investigation is needed into individual-level factors associated with coverage.

Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England.

BACKGROUND: Reduction in the prevalence of vaccine type HPV infection in young women is an early indication of the impact of the HPV immunisation programme and a necessary outcome if the subsequent impact on cervical cancer is to be realised. METHODS: Residual vulva-vaginal swab (VVS) specimens from young women aged 16-24 years undergoing chlamydia screening in community sexual health services (formerly known as family planning clinics), general practice (GP), and youth clinics in 2010-2012 were submitted from 10 laboratories in seven regions around England. These specimens were linked to demographic and sexual behaviour data reported with the chlamydia test, anonymised, and tested for type-specific HPV DNA using a multiplex PCR and Luminex-based genotyping test. Estimated immunisation coverage was calculated and findings were compared to a baseline survey conducted prior to the introduction of HPV immunisation in 2008. RESULTS: A total of 4664 eligible specimens were collected and 4178 had a valid test result. The post-immunisation prevalence of HPV 16/18 infection was lowest in this youngest age group (16-18 years) and increased with age. This increase with age was a reversal of the pattern seen prior to immunisation and was inversely associated with estimates of age-specific immunisation coverage (65% for 16-18 year olds). The prevalence of HPV 16/18 infection in the post-immunisation survey was 6.5% amongst 16-18 year olds, compared to 19.1% in the similar survey conducted prior to the introduction of HPV immunisation. CONCLUSIONS: These findings are the first indication that the national HPV immunisation programme is successfully preventing HPV 16/18 infection in sexually active young women in England. The reductions seen suggest, for the estimated coverage, high vaccine effectiveness and some herd-protection benefits. Continued surveillance is needed to determine the effects of immunisation on non-vaccine HPV types.

Comparing the performance of six human papillomavirus tests in a screening population.

BACKGROUND: Several new assays have been developed for high-risk HPV testing of cervical samples; we compare six HPV tests in a screening population. METHODS: Residual material from liquid-based PreservCyt samples was assayed. Four tests (Hybrid Capture 2, Cobas, Abbott and Becton-Dickinson (BD)) measured HPV DNA while two used RNA (APTIMA and NorChip). RESULTS: Positivity rates ranged from 13.4 to 16.3% for the DNA-based tests with a significantly lower positivity rate for the Abbott assay. The Gen-Probe APTIMA assay was positive in 10.3% of women, which was significantly lower than all the DNA tests; the NorChip PreTect HPV-Proofer test was much lower at 5.2%. 40 CIN2+ cases were identified, of which 19 were CIN3+. All CIN3+ cases were HPV positive by all tests except for one, which was negative by the Abbott assay and five which were negative by the NorChip test. CONCLUSION: All HPV tests except NorChip showed high sensitivity for high-grade lesions positive by cytology, suggesting co-testing is unnecessary when using HPV tests. Positivity rates in cytology-negative specimens were similar for the DNA-based tests, but lower for the APTIMA test suggesting this maintains the high sensitivity of DNA tests, but with better specificity.

Characteristics of HPV infection over time in European women who are HIV-1 positive.

OBJECTIVE: The objectives of the study were to investigate high-risk human papillomavirus (HR-HPV) infection and type distribution in women infected with HIV-1, and to determine the relevance of HR-HPV positivity and persistence/loss to the development of high-grade cervical disease. DESIGN: A total of 518 European women infected with HIV attending for routine gynaecological care consented to 6-monthly follow-up visits over 3 years, with surveillance of cytology, colposcopy and histopathology, where relevant, and longer follow-up, where possible. SETTING: European women infected with HIV attending for routine gynaecological care. POPULATION OR SAMPLE: 518 European women infected with HIV attending for gynaecological care in 6 hospital-based European centres - Dublin, Edinburgh, London, Milan, Paris, and Warsaw. METHODS: Cervical screening was achieved by liquid-based cytology (LBC) of brush samples in PreservCyt® medium. The HPV testing of residual samples was performed by Hybrid-Capture II, with genotyping of positives using the HPV Line Blot Assay. Histology results were accessed where available. MAIN OUTCOME MEASURES: Description of high risk human papillomavirus (HR-HPV) infection and type distribution in HIV-1 infected women. RESULTS: The estimated prevalence at baseline of any HR-HPV type was 49.5% (46.3-52.8%): 10.2% for HPV 16 and 4.3% for HPV 18. The prevalence increased with increasing immunosuppression. Multiple infections were detected in 26.8%. HR-HPV genotypes were detected in 34.9% of cases with normal cytology, in 77.2% of cases with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASCUS/LSIL) and in 90.8% of cases with high-grade SIL (HSIL). The prevalence of HPV 16 in HSIL was 38.5%, with the three most common types thereafter having prevalence rates of 19.2% (HPV 58), 19.2% (HPV 53) and 16.6% (HPV 52). The overall persistence of any high-risk type was 55.8%. We found that 6 months persistence of HPV 16 occurred in 24 women. Seven cases of high-grade cervical disease developed, and all were associated with initial/persistent HR-HPV positivity. CONCLUSIONS: A wide diversity of HPV types was evident, and multiple infections were common. Detection or persistence of any HR-HPV was associated with a very low incidence of subsequent high-grade disease.

A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population.

Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence-based skin cancer surveillance program.

Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort.

BACKGROUND: The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy. METHODS: Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer. RESULTS: In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions. CONCLUSION: For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial.

BACKGROUND: Cervical screening identifies many women with low-grade abnormalities. In vitro and in vivo studies have shown that diindolylmethane (DIM) could potentially halt (cervical) carcinogenesis. We report on a randomised controlled trial of the effect of DIM in women with low-grade cervical cytological abnormalities. METHODS: We conducted a pragmatic double-blind, randomised controlled trial of 150 mg DIM (from BioResponse DIM) or placebo daily for 6 months in women with newly diagnosed, low-grade cytological abnormalities. Randomisation was in the ratio 2 (DIM) to 1 (placebo). All women were invited for colposcopy at 6 months with biopsy of any abnormality. RESULTS: Of the 551 randomised women available for analysis, 9% on DIM and 12% on placebo had cervical intraepithelial neoplasia-2 (CIN2) or worse after 6-month supplementation (risk ratio (RR) 0.7 (95% confidence interval (CI): 0.4-1.2)), whereas 4.6% and 5.1%, respectively, had CIN3 or worse (RR 0.9 (95% CI: 0.4-2.0)). A total of 27.3% of women on DIM and 34.3% on placebo had no sign of disease (negative cytology, colposcopy and human papilloma virus (HPV) tests) at 6 months (RR 0.8 (95% CI: 0.6-1.0)). Of those HPV-positive at baseline, 69% (114 out of 166) of the DIM group were positive at 6 months compared with 61% (43 out of 71) of the placebo group: RR 1.1 (95% CI: 0.9-1.4). Diindolylmethane supplementation was well tolerated. CONCLUSION: The results suggest that short-term DIM supplementation (150 mg day(-1)) is well tolerated, but is unlikely to have an effect on cytology or HPV infection. Uncertainty remains regarding its effect on CIN2+.

HPV self-sampling as an alternative strategy in non-attenders for cervical screening - a randomised controlled trial.

BACKGROUND: A randomised trial to ascertain whether women who do not attend for cervical screening are more likely to respond to the opportunity to collect a self-sample for human papillomavirus (HPV) testing, or to a further invitation to attend for cervical screening. METHODS: The study was carried out in a Primary Care Trust (PCT) in London between June 2009 and December 2009. In total, 3000 women were randomly selected from persistent non-responders (i.e., who had not responded to at least two invitations to attend for screening). The women were randomised on a 1 : 1 basis to either receive an HPV self-sampling kit or a further invitation to attend for cervical cytology. The main outcome measures were (1) percentage of women attending for cervical cytology compared with those returning a self-sample HPV test or attending for cytology subsequent to receiving the kit and (2) percentage of those testing positive for HPV who attended further investigation. RESULTS: The total response in the self-sampling group for screening was 10.2%. Of the 1500 women in the control group sent a further invitation for cervical screening, 4.5% attended for cytology screening. This difference is highly statistically significant (P<0.0001). Of the 8 women who tested positive for HPV, 7 attended for a cervical smear and had a concurrent colposcopy. Three of these (43%) had high-grade disease (defined as CIN 2+), with one found to have an invasive cancer (stage 1b) and one CIN 3. CONCLUSIONS: The value of this intervention relies on the detection of high-grade CIN and early stage cancer with a good prognosis. The relatively high yield of abnormalities found is consistent with that expected among a hard to reach and relatively high-risk group of women. Our study suggests that self-sampling could increase participation among non-responders in England, but further work is needed to ascertain whether the low response rate seen here is likely to be representative of the rest of the country. Other studies are needed to investigate the response to self-sampling in different demographic and geographic settings.

Long-term follow-up of cervical disease in women screened by cytology and HPV testing: results from the HART study.

BACKGROUND: Several studies have shown that testing for high-risk human papillomavirus (HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with a somewhat lower specificity. METHODS: We obtained follow-up results, with at least one smear after participation in the HART study, which compared HPV testing (HC-II) with cytology as a primary screening modality. RESULTS: With a median follow-up of 6 years, 42 additional cases of CIN2+ were identified; women who were HPV positive at baseline were more likely to develop CIN2+ than those who were HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3-31.6)) and the risk increased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU) <1), the HR (95% CI) was 5.4 (1.6, 18.2) for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or = 10. Positive cytology (borderline or worse compared with negative) was also predictive of developing CIN2, although to a lesser extent (HR 8.7; 95% CI (4.5-17.1)). Only one case of CIN3 and three cases of CIN2 were found in women who showed a positive cytology result but were HPV negative at baseline. CONCLUSION: After 5 years of follow-up, CIN2+ occurred in 0.23% of women who were HPV negative at baseline compared with 0.48% of women who showed a negative cytology result, indicating a much longer low-risk interval for CIN2+ after HPV testing.

Melanoma in organ transplant recipients: clinicopathological features and outcome in 100 cases.

Organ transplant recipients have a higher incidence of melanoma compared to the general population but the prognosis of this potentially fatal skin cancer in this group of patients has not yet been established. To address this, we undertook a multicenter retrospective analysis to assess outcome for 100 melanomas (91 posttransplant and 9 pretransplant) in 95 individuals. Data were collected in 14 specialist transplant dermatology clinics across Europe belonging to the Skin Care in Organ Transplant Patients, Europe (SCOPE) Network, and compared with age, sex, tumor thickness and ulceration status-matched controls from the American Joint Committee on Cancer (AJCC) melanoma database. Outcome for posttransplant melanoma was similar to that of the general population for T1 and T2 tumors (< or = 2 mm thickness); but was significantly worse for T3 and T4 tumors (> 2 mm thickness); all nine individuals with a pretransplant melanoma survived without disease recurrence following organ transplantation. These data have implications for both cutaneous surveillance in organ transplant recipients and management of transplant-associated melanoma.

Beta-papillomaviruses and psoriasis: an intra-patient comparison of human papillomavirus carriage in skin and hair.

BACKGROUND: Human papillomaviruses (HPVs) of the beta genus (beta-PV), especially HPV5 and HPV36, are proposed to play a pathogenic role in psoriasis, but many previous studies have failed to control for potential confounders, including treatment. OBJECTIVES: To re-examine the relationship between beta-PV and psoriasis addressing limitations present in previous studies and analyse intra-patient concordance for carriage of HPV. METHODS: Plucked eyebrow hairs and forearm skin scrapes were collected from 20 newly diagnosed, previously untreated adult patients with psoriasis and 23 normal controls. A combination of type-specific and degenerate polymerase chain reaction methods was used to achieve comprehensive HPV DNA detection. RESULTS: The prevalence of HPV in hair and skin from psoriasis patients was higher than in controls (83.3% vs. 46.7%, respectively, P < 0.03 corrected for age and clustering). HPV5 or HPV36 were not over-represented. The profile of diverse beta-PV types was comparable in the two groups. Intra-patient concordance for HPV DNA at separate sites was high (P < 0.00001). CONCLUSIONS: Our data do not support a specific causal role for HPV5 or HPV36 in psoriasis, but suggest that psoriatic skin may be more permissive for viral presence than normal skin. High intra-patient concordance for specific HPV types at separate sites, together with the ubiquity of HPV DNA in normal human skin, suggests that an individual becomes colonized with a particular beta-PV profile presumably to the exclusion of other types. To what extent this HPV profile is then causal in the subsequent development of hyperproliferative skin disease is unknown.