High prevalence of HPV 51 in an unvaccinated population and implications for HPV vaccines

Human papillomavirus (HPV) is detected in 99.7% of cervical cancers. Current vaccines target types 16 and 18. Prior to vaccination implementation, a prospective cohort study was conducted to determine baseline HPV prevalence in unvaccinated women in Wales; after HPV16 and HPV18, HPV 51 was found to be most prevalent. This study aimed to re-assess the unexpected high prevalence of HPV 51 and consider its potential for type-replacement. Two hundred HPV 51 positive samples underwent re-analysis by repeating the original methodology using HPV 51 GP5+/6+ PCR-enzyme immunoassay, and additionally a novel assay of HPV 51 E7 PCR. Data were correlated with age, social deprivation and cytology. Direct repeat of HPV 51 PCR-EIA identified 146/195 (75.0%) samples as HPV 51 positive; E7 PCR identified 166/195 (85.1%) samples as HPV 51 positive. HPV 51 prevalence increased with cytological grade. The prevalence of HPV 51 in the pre-vaccinated population was truly high. E7 DNA assays may offer increased specificity for HPV genotyping. Cross-protection of current vaccines against less-prevalent HPV types warrants further study. This study highlights the need for longitudinal investigation into the prevalence of non-vaccine HPV types, especially those phylogenetically different to vaccine types for potential type-replacement. Ongoing surveillance will inform future vaccines

Human Papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting. Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing. Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n = 30), median E2 methylation was significantly higher in patients who responded (P ≤ 0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n = 33), median E2 methylation was lower in patients who responded to treatment (P = 0.03; not significant after Bonferroni correction); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity. Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial

Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multi-centre, randomised, phase II trial (RT3VIN)

Objective To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. Design A prospective, open, randomised multicentre trial. Setting 32 general hospitals located in Wales and England. Population or Sample 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). Methods After 24 weeks of treatment, complete responders were followed up at 6‐monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. Main outcome measures Time to histologically confirmed disease recurrence (any grade of VIN). Results The median length of follow up was 18.4 months. At 18 months, more participants were VIN‐free in the cidofovir arm: 94% (95% CI 78.2–98.5) versus 71.6% (95% CI 52.0–84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95–12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96–12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+. Conclusions Long‐term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs Tweetable abstract Long‐term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod

Understanding context in knowledge translation: a concept analysis study protocol

AimTo conduct a concept analysis of clinical practice contexts (work environments) that facilitate or militate against the uptake of research evidence by healthcare professionals in clinical practice. This will involve developing a clear definition of context by describing its features, domains and defining characteristics.BackgroundThe context where clinical care is delivered influences that care. While research shows that context is important to knowledge translation (implementation), we lack conceptual clarity on what is context, which contextual factors probably modify the effect of knowledge translation interventions (and hence should be considered when designing interventions) and which contextual factors themselves could be targeted as part of a knowledge translation intervention (context modification).DesignConcept analysis.MethodsThe Walker and Avant concept analysis method, comprised of eight systematic steps, will be used: (1) concept selection; (2) determination of aims; (3) identification of uses of context; (4) determination of defining attributes of context; (5) identification/construction of a model case of context; (6) identification/construction of additional cases of context; (7) identification/construction of antecedents and consequences of context; and (8) definition of empirical referents of context. This study is funded by the Canadian Institutes of Health Research (January 2014).DiscussionThis study will result in a much needed framework of context for knowledge translation, which identifies specific elements that, if assessed and used to tailor knowledge translation activities, will result in increased research use by nurses and other healthcare professionals in clinical practice, ultimately leading to better patient care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111196/1/jan12574.pd

Identification of Human Papillomavirus Type 58 Lineages and the Distribution Worldwide

Background. Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. Methods and results. This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014–6539) and LCR (nucleotides 7257–7429 and 7540–52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. Conclusions. HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study

Geographical Distribution and Risk Association of Human Papillomavirus Genotype 52–Variant Lineages

Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%–5.5% ; Pcorrected &lt; .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name “Asian lineage” be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B

Power Doppler in the assessment of pelvic masses in a low risk group

Discrimination between benign and malignant adnexal masses aids in optimising the management of women with pelvic tumours. A grading system incorporating grey-scale and power Doppler measurements might increase the accuracy of pre-operative assessment. The present study aimed to assess the sensitivity and specificity of a grading system including grey-scale and power Doppler findings. A total of 179 women who had undergone power Doppler Ultrasound for a pelvic mass between April 2001 and March 2003 were identified. Masses were surveyed by grey-scale and power Doppler and graded in relation to the estimated risk of malignancy. Clinicians were provided with the findings. The results were compared with the findings at surgery. A total of 74.3% were premenopausal. Some 94.4% (n = 169) had benign; 1.7% borderline and 3.9% malignant histology. A total of 69% underwent surgery. Specificity was 72.2 - 95.9%; sensitivity 55.6 - 88.9% and negative predictive value 97.6 - 99.2%. Power Doppler as an additional diagnostic aid may help the clinician in the management of pelvic masses. Further research is needed to clarify sensitivity and specificity

Human papillomavirus infection in Barrett's oesophagus in the UK: an infrequent event

Background Human papillomavirus (HPV) infection has been reported in squamous cell carcinomas of the oesophagus and has been recently described in Barrett's oesophagus, a premalignant condition which may give rise to oesophageal adenocarcinoma. Objectives To investigate HPV infection in Barrett's oesophagus in a UK population. Study design DNA was extracted from 73 Barrett's oesophagus biopsies and examined for the presence of DNA for 14 high risk (HR) and 6 low risk (LR) HPV types. Results HPV DNA was present in only 1 of 73 samples; genotyping indicated this was a high risk type 51 infection. Conclusions HPV infection appears unlikely to be a significant factor in the aetiology of Barrett's oesophagus in the UK