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    ABSTRACT: Background HR HPV genotypes when assayed collectively, achieve high sensitivity but low specificity for the prediction of CIN2+. Knowledge of the specific genotypes in an infection may facilitate the use of HR HPV detection in routine clinical practice. Objectives To compare the rate of HR HPV detection and the accuracy of CIN2+ prediction between PapType test (Genera Biosystems) and other commercially available HR HPV assays, and to examine the value of full HPV genotyping. Study design. PreservCyt samples from 1099 women referred for abnormal cervical cytology were used. CIN2+ was chosen as the primary end-point but CIN3+ was also evaluated. A hierarchy of HR HPV genotypes was created using PPV and this was used to create 3 groups of genotypes with potentially different management. Results The PapType assay has a specificity of 22.4% and a sensitivity of 94.6% for CIN2+ prediction. Classification into Groups A (HPV33 and HPV16, very highly predictive), B (HPV31, 18, 52, 35, 58, 51 highly predictive) and C (HPV68, 45, 39, 66, 56, 59, intermediate predictive) could double the specificity (44.5%) but only slightly reduce the sensitivity for CIN2+ (91.5%) and CIN3+ (94.0%). Conclusions The PapType assay is a simple, reproducible and effective test for HR HPV detection and genotyping. HPV 33 was found to have a very high PPV and should therefore be managed as for HPV16.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 05/2014; DOI:10.1016/j.jcv.2014.02.002
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    ABSTRACT: Objective Testing for high risk human papillomavirus (HR-HPV) is increasing, however due to limitations in specificity there remains a need for better triage tests. Research efforts have focused recently on methylation of human genes which show promise as diagnostic classifiers. Methods Methylation of 26 genes: APC, CADM1, CCND2, CDH13, CDKN2A, CTNNB1, DAPK1, DPYS, EDNRB, EPB41L3, ESR1, GSTP1, HIN1, JAM3, LMX1, MAL, MDR1, PAX1, PTGS2, RARB, RASSF1, SLIT2, SOX1, SPARC, TERT and TWIST1 was measured by pyrosequencing in cytology specimens from a pilot set of women with normal or cervical intraepithelial neoplasia grade 3 (CIN3) histology. Six genes were selected for testing in Predictors 1, a colposcopy referral study comprising 799 women. The three genes EPB41L3, DPYS and MAL were further tested in a second colposcopy referral study, Predictors 2, comprising 884 women. Results The six genes selected from the pilot: EPB41L3, EDNRB, LMX1, DPYS, MAL and CADM1 showed significantly elevated methylation in CIN2 and CIN3 (CIN2/3) versus ≤ CIN1 in Predictors 1 (p < 0.01). Highest methylation was observed in cancer tissues. EPB41L3 methylation was the best single classifier of CIN2/3 in both HR-HPV positive (p < 0.0001) and negative samples (p = 0.02). Logistic regression modeling showed that other genes did not add significantly to EPB41L3 and in Predictors 2, its classifier value was validated with AUC 0.69 (95% CI 0.65-0.73). Conclusion Several methylated genes show promise for detecting CIN2/3 of which EPB41L3 seems the best. Methylated human gene biomarkers used in combination may be clinically useful for triage of women with HR-HPV infections.
    Gynecologic Oncology 03/2014; DOI:10.1016/j.ygyno.2014.02.001
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    ABSTRACT: Surveillance guidelines for the management of Familial Colorectal Cancer (FCC), a dominant family history of colorectal cancer in which the Polyposis syndromes and Lynch syndrome have been excluded, are not firmly established. The outcome of colonoscopic surveillance is studied using data from six centres. DNA mismatch repair deficiency was excluded by genetic testing. Families were classified as FCC type X if they fulfilled the original Amsterdam criteria (AC) and late onset (LOFCC) if they fulfilled the AC apart from not having a cancer aged under50. The most advanced findings on colonoscopy were analysed. 1585 individuals (median age 47.3, 44% male) from 530 FCC families (349 FCC type X) underwent a total of 4992 colonoscopies with 7904 patient-years of follow-up. Results for FCC type X and LOFCC were very similar. At baseline22 prevalent asymptomatic colorectal cancers were diagnosed, 120 (7.6%) individuals had high-risk adenomas and 225 (14.2%) simple adenomas. 1088 individualshad further colonoscopy (median follow-up of 6.2 years).Of nine individuals diagnosed with cancer. 8 had a previous history of at least one polyp/adenoma. High-risk adenomas were detected in 92 (8.7%) and multiple adenomas were detected in 20 (1.9%) individuals. Both FCC type X and LOFCC have a high prevalence of colorectal cancers and on follow-up develop high-risk adenomas (including multiple adenomas), but infrequent interval cancers. They should be managed similarly with five-yearly colonoscopies undertaken from between 30-40 with more intensive surveillance in individuals developing multiple or high-risk adenomas.
    International Journal of Cancer 02/2014; 134(4). DOI:10.1002/ijc.28397
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    ABSTRACT: High risk human papillomavirus (HR-HPV) infection is common and only a small minority of infections become persistent and lead to cervical cancers. Women positive for HR-HPV usually require a second test to avoid unnecessary colposcopies and over treatment. Elevated DNA methylation of HR-HPV L1 and L2 genes in high grade disease has emerged as a promising molecular triage tool. Our aim was to accurately measure methylation levels at selected CpG positions in the HPV18, HPV31 and HPV33 genomes. We focused on the L2, L1, URR and E6 regions because these were previously shown to be interesting areas for study. Pyrosequencing was used to measure methylation in 208 HPV18, 207 HPV31, and 126 HPV33 positive women selected from a London colposcopy referral population. After adjustment for multiple testing, at FDR 5%, elevated methylation was significantly associated with cervical intraepithelial neoplasia grades 2 or worse (CIN2+) in all investigated CpGs in HPV18 L2 and L1. Two of 6 L2 and 12 of 15 L1 sites in HPV31 and 6 of 8 L2 and 3 of 13 L1 sites in HPV33 showed significantly elevated methylation in CIN2+. Methylation of CpG sites in the URR and E6 region of the HPV types was low and most differences were not significant. Elevated methylation of CpG sites in the L1 and L2 regions of HPV18, HPV31 and HPV33 is associated with CIN2+ and a panel test may be useful for triage of women with HR-HPV infections.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 01/2014; DOI:10.1016/j.jcv.2013.12.014
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    ABSTRACT: Background:Cervical screening consumes substantial resources, but little is known about utilization in the United States or compliance with guideline recommendations. Methods:To describe population screening coverage, utilization and outcomes and examine time trends from 2008 to 2011, cervical cytology reports from women residing in New Mexico (981,063 tests from 511,381 women) were evaluated. Results:From 2008-2011 cervical screening utilization decreased at all ages, but especially in younger women, with a two-thirds reduction at ages 15-20 years. 94% of women aged 25-29 years were screened within 48 months but coverage decreased at older ages, to 69% at 45-49 years and 55% at 60-64 years. Intervals between screening tests were significantly longer in 2011 compared to 2008 (hazard ratio = 1.23, 95% CI = 1.22-1.24) although the commonest rescreening interval was 13 months. In 2011, 91.9% of screening tests for women aged 21-65 years were negative, 6.6% showed minor abnormalities, and 1.0% high grade abnormalities. .High grade abnormality rates were relatively constant over time, but minor abnormalities and atypical cells cannot rule out high-grade (ASC-H) were increasing. Conclusions:This population-based evaluation of cervical screening shows high coverage under the age of 40 years but lower levels in older women. Screening under age 21 years is becoming less common and screening intervals are lengthening, reflecting updates in national screening guidelines. Impact:Assessment of cervical screening intervals and population outcomes is essential for accurately estimating the impact and effectiveness of changing recommendations and vaccination against human papillomavirus infections.
    Cancer Epidemiology Biomarkers & Prevention 12/2013; 23(5). DOI:10.1158/1055-9965.EPI-13-0973
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    ABSTRACT: Colorectal cancer (CRC) is the second commonest cancer in England. Incidence rates for colorectal adenomas and advanced colorectal neoplasia are higher in men than in women of all age groups. The male-to-female ratio for CRC incidence rates differs for different parts of the large bowel. To summarize the current evidence on colorectal screening and prevention, focussing on potential differences in benefits between sexes and colorectal sites. , We reviewed the evidence from randomized controlled trials (RCTs) of the impact of different screening approaches on CRC incidence and mortality, overall, for each sex separately, and for subsites of the large bowel. (ii) We reviewed studies comparing detection parameters for faecal immunochemical tests for haemoglobin (FIT) with guaiac FOBt (gFOBt). (iii) The role of aspirin in CRC prevention in the general population was reviewed using evidence from RCTs, with specific emphasis on the differences observed between sexes and lesion site. (i) Our intention-to-treat random-effects meta-analysis showed that once-only flexible sigmoidoscopy (FS) screening performed on average-risk individuals aged 55 + decreased CRC incidence by 18% and mortality by 28%, but sex-specific results were lacking. (ii) Modern quantitative FIT were superior to qualitative gFOBt in average-risk population screening in their ability to discriminate between individuals with and without colorectal neoplasia. Some recent FIT studies suggest varying operating characteristics in men and women. (iii) Evidence of an effect of aspirin on the incidence of CRC (in particular, proximal disease) in both sexes aged 40 and over at average-risk of CRC is emerging. We encourage researchers of CRC screening and prevention to publish their results by sex where possible. Pilot studies should be undertaken before implementation of quantitative FIT in a national screening programme to establish the appropriate threshold. Finally, individual risk assessment for CRC and non-CRC events, will be necessary to make an informed decision on whether a patient should receive aspirin chemoprevention.
    Journal of Medical Screening 11/2013; 20(3):125-48. DOI:10.1177/0969141313501292
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    ABSTRACT: Background. Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent. Methods. Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations. Results. In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74. Conclusions. The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.
    The Journal of Infectious Diseases 11/2013; 208(9):1391-1396. DOI:10.1093/infdis/jit360
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Adjuvant endocrine therapy beyond 5 years reduces recurrence in patients with estrogen receptor-positive breast cancer. We have previously shown that immunohistochemical markers (IHC4) and two gene expression profile tests (recurrence score [RS] and PAM50 risk of recurrence [ROR]) are associated with time to distant recurrence, and we have now assessed the value of each of these scores and routine clinical variables for predicting outcome, specifically in years 5 to 10. We used univariate and multivariable proportional hazards models to determine the prognostic value of all variables and scores (IHC4, RS, ROR) for distant recurrence, separately in years 0 to 5 and specifically for years 5 to 10 for all patients. All statistical tests were two-sided. Nodal status and tumor size were at least as strong in years 5 to 10 as in years 0 to 5 (nodal status, years 5-10: χ(2) = 21.72 vs years 0-5: χ(2) = 11.08, both P < .001; tumor size, years 5-10: χ(2) = 10.52 vs years 0-5: χ(2) = 10.82, both P = .001). Ki67 and the overall IHC4 score were the only statistically significant biomarkers related to distant recurrence univariablely in the 5 to 10 year period (χ(2) = 8.67, χ(2) = 13.22, respectively). The ROR score was the strongest molecular prognostic factor in the late follow-up period (χ(2) = 16.29; P < .001), whereas IHC4 (χ(2) = 7.41) and RS (χ(2) = 5.55) were only weakly prognostic in this period. Similar results were seen for all subgroups and for all recurrences. None of the IHC4 markers provided statistically significant prognostic information in years 5 to 10, except for nodal status and tumor size. ROR gave the strongest prognostic information in years 5 to 10. These results may help select patients who could benefit most from hormonal therapy beyond 5 years of treatment.
    CancerSpectrum Knowledge Environment 09/2013; 105(19). DOI:10.1093/jnci/djt244
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    ABSTRACT: Human papillomavirus testing has been shown to be far more sensitive and robust in detecting cervical intraepithelial neoplasia 2 and above (and cervical intraepithelial neoplasia 3 and above) for cervical screening than approaches based on either cytology or visual inspection; however, there are a number of issues that need to be overcome if it is to substantially reduce the morbidity and mortality associated with cervical cancer at the population level. The two main issues are coverage (increasing the number of women who participate in screening) and the management of women who test positive for high-risk human papillomavirus. This article will review the potential for vaginal self-collection to improve coverage and the options for triage of high-risk human papillomavirus-positive women in high-resource and low-resource settings.
    Women s Health 09/2013; 9(5):443-52. DOI:10.2217/whe.13.48
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    ABSTRACT: DNA methylation changes in human papillomavirus type 16 (HPV16) DNA are common and might be important for identifying women at increased risk of cervical cancer. Using recently published data from Costa Rica we developed a classification score to differentiate women with cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) from those with no evident high grade lesions. Here we aim to investigate the performance of the score using data from the UK. Exfoliated cervical cells at baseline and six-months follow-up were analyzed in 84 women selected from a randomized clinical trial of women undergoing surveillance for low grade cytology. Selection of women for the methylation study was based on detectable HPV16 in the baseline sample. Purified DNA was bisulfite converted, amplified and pyrosequenced at selected CpG sites in the viral genome (URR, E6, L1 and L2), with blinding of laboratory personnel to the clinical data. The primary measure was a predefined score combining the mean methylation in L1 and any methylation in L2. At the second follow-up visit 73/84 (87%) women were HPV16 positive and of these 25 had a histo-pathological diagnosis of CIN2/3. The score was significantly associated with CIN2/3 (area under curve = 0.74, p=0.002). For a cut-off with 92% sensitivity, colposcopy could have been avoided in 40% (95%CI 27-54%) of HPV16 positive women without CIN2/3; positive predictive value was 44% (32-58%) and negative predictive value was 90% (71-97%). We conclude that quantitative DNA methylation assays could help to improve triage among HPV16 positive women.
    International Journal of Cancer 08/2013; 133(3). DOI:10.1002/ijc.28050
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