Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test

A C K N O W L E D G E M E N T S The authors wish to acknowledge Jo Morrison for her clinical and editorial advice, Jane Hayes f or designing the search strategy and Gail Quinn, Clare Jess and Tracey Bishop for their contribution to the editorial process.This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors andd o not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Changes in HPV prevalence following a national bivalent HPV vaccination programme in Scotland: a 7-year cross-sectional study

Background: On Sept 1, 2008, Scotland launched routine vaccination for human papillomavirus (HPV) types 16 and 18, targeted at 12–13-year-old girls, of whom 92·4% were fully vaccinated in 2008–09. In this study, we report on vaccine effectiveness of the bivalent vaccine in these vaccinated women who attended for routine cervical screening at age 20–21 years. Methods: In this 7-year cross-sectional study (covering birth cohorts 1988–1995), we sampled approximately 1000 samples per year from those attending cervical screening at age 20–21 years and tested each for HPV. By linkage to vaccination records we ascertained prevalence by birth cohort and vaccination status. Estimates of vaccine effectiveness for HPV types 16 and 18, HPV types 31, 33, and 45, other high-risk types, and any HPV were calculated using logistic regression. Findings: In total, 8584 samples were HPV genotyped. Prevalence of HPV types 16 and 18 reduced substantially from 30·0% (95% CI 26·9–33·1) in the 1988 cohort to 4·5% (3·5–5·7) in the 1995 cohort, giving a vaccine effectiveness of 89·1% (85·1–92·3) for those vaccinated at age 12–13 years. All cross-protective types showed significant vaccine effectiveness (HPV type 31, 93·8% [95% CI 83·8–98·5]; HPV type 33, 79·1% [64·2–89·0]; HPV type 45, 82·6% [61·5–93·9]). Unvaccinated individuals born in 1995 had a reduced odds of HPV types 16 and 18 infection compared with those born in 1988 (adjusted odds ratio 0·13 [95% CI 0·06–0·28]) and reduced odds of HPV types 31, 33, and 45 (odds ratio 0·45 [0·23–0·89]). Interpretation: Bivalent vaccination has led to a startling reduction in vaccine and cross-protective HPV types 7 years after vaccination. There is also evidence of herd protection against the vaccine-specific and cross-protective types in unvaccinated individuals born in 1995. These findings should be considered in cost-effectiveness models informing vaccine choice and models to shape the future of cervical screening programmes

Increased risk of HPV-associated genital cancers in men and women as a consequence of pre-invasive disease

To assess the excess risk of HPV‐associated cancer (HPVaC) in two at‐risk groups – women with a previous diagnosis of high grade cervical intraepithelial neoplasia (CIN3) and both men and women treated for non‐cervical pre‐invasive ano‐genital disease. All CIN3 cases diagnosed in 1989‐2015 in Scotland were extracted from the Scottish cancer registry (SMR06). All cases of pre‐invasive penile, anal, vulval, and vaginal disease diagnosed in 1990‐2015 were identified within the NHS pathology databases in the two largest NHS health boards in Scotland. Both were linked to SMR06 to extract subsequent incidence of HPVaC following the diagnosis of CIN3 or pre‐invasive disease. Standardised incidence ratios were calculated for the risk of acquiring HPVaC for the two at‐risk groups compared with the general Scottish population. Among 69714 females in Scotland diagnosed with CIN3 (890360.9 person‐years), 179 developed non‐cervical HPVaC. CIN3 cases were at 3.2‐fold (95% CI: 2.7 to 3.7) increased risk of developing non‐cervical HPVaC, compared to the general female population. Among 1235 patients diagnosed with non‐cervical pre‐invasive disease (9667.4 person‐years), 47 developed HPVaC. Individuals with non‐cervical pre‐invasive disease had a substantially increased risk of developing HPVaC ‐ 15.5‐fold (95% CI: 11.1 to 21.1) increased risk for females and 28‐fold (11.3 to 57.7) increased risk for males. We report a significant additional risk of HPV‐associated cancer in those have been diagnosed with pre‐invasive HPV‐associated lesions including but not confined to the cervix. Uncovering the natural history of pre‐invasive disease has potential for determining screening, prevention and treatment

Measuring the psychosocial burden in women with low-grade abnormal cervical cytology in the TOMBOLA trial: psychometric properties of the Process and Outcome Specific Measure (POSM)

Background There is a need for an instrument to measure the psychosocial burden of receiving an abnormal cervical cytology result which can be used regardless of the clinical management women receive. Methods 3331 women completed the POSM as part of baseline psychosocial assessment in a trial of management of low grade cervical cytological abnormalities. Factor analysis and reliability assessment of the POSM were conducted. Results Two factors were extracted from the POSM: Factor 1, containing items related to worry; and Factor 2 containing items relating to satisfaction with information and support received and change in the way women felt about themselves. Factor 1 had good reliability (Cronbach’s alpha 0.769), however reliability of the Factor 2 was poorer (0.482). Data collected at four subsequent time points demonstrated that the factor structure was stable over time. Conclusion This study demonstrates the presence and reliability of a scale measuring worries within the POSM. This analysis will inform its future use in this population and in other related contexts

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

UK national survey of the management of vaginal intraepithelial neoplasia

Vaginal intraepithelial neoplasia (VaIN) is less common than intraepithelial neoplasia at other non-cervical sites and can be challenging to manage. This survey describes current clinical practice by colposcopists in the UK. An online questionnaire was emailed to all the lead colposcopists in U.K. A total of 86 (43%) responses were obtained. The median number of cases of VaIN seen in a year was five (range 0–100. Most clinics (95%) managed low grade VaIN conservatively. Local vaginal mucosal excision was the most common surgical procedure. Half of respondents adopted observation, although 64% of the units referred cases to a cancer centre. More than half used a combination of cytology and colposcopy for follow-up; only two reported using Human papilloma virus testing. Seventy-seven of eighty-six lead colposcopists did not have a local guideline and would support national guidance. Treatment differed across the UK with no agreed management guidelines.Impact statement What is already known on the subject? Vaginal intraepithelial neoplasia (VaIN) is a pre-cancerous condition of lower genital tract and usually co-exists with cervical intraepithelial neoplasia (CIN) rather than in isolation. Unlike CIN, VaIN can be extremely challenging to manage in view of its anatomical proximity to bladder and bowel and also difficulty in accessing fornices. If diagnosed during the definitive management of CIN at the time of hysterectomy and confined to the upper vagina, it could be surgically treated at the same time. VaIN can be more challenging post-hysterectomy, especially following a failed medical and conservation option. Various treatment options are adopted for management of VaIN with no standardisation of care. What do the results of this study add? A national survey was conducted to assess the management of VaIN amongst lead colposcopists. The national survey has added valuable results, despite a response rate of only 43%. The survey confirmed conservative approach to low grade VaIN but differing treatment for high grade VaIN. What are the implications of these findings for clinical practice and/or further research? This clearly calls for the implementation of a national guideline in the UK to standardise management of VaIN, though it may be quite challenging. The survey could help inform implementation of HrHPV testing in recurrent or persistent VaIN