Given the lower specificity for high-grade cervical lesions of high-risk human papillomavirus (hrHPV) testing compared to cytology, additional triage testing for hrHPV test-positive women is needed to detect high-grade cervical lesions. Here, we tested whether combined methylation analysis for cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL), both functionally involved in cervical carcinogenesis, could serve as such a triage marker. Four quantitative methylation-specific PCRs (qMSP), two for CADM1 (regions M12 and M18) and MAL (regions M1 and M2) each, were applied to 261 cervical tissue specimens ranging from no neoplasia to carcinoma. When qMSPs were combined and positivity for at least one of the qMSPs in the combination was taken into account, the highest positivity rates for cervical intraepithelial neoplasia grade 3 (CIN3) lesions (97%) and squamous cell-and adeno-carcinomas (99%) were obtained by combining a single CADM1 marker with a single MAL marker. Subsequent qMSP analysis of 70 GP51/61-PCR hrHPV-positive scrapings revealed that a two-marker panel consisting of CADM1-M18 and MAL-M1 was most discriminative, detecting 90% of women with CIN3 (n 5 30), whereas it showed a positive result in only 13.5% of women without cervical disease (n 5 40). Finally, we applied hrHPV GP51/61-PCR testing followed by CADM1-M18/MAL-M1 methylation analysis to a cohort of 79 women visiting the outpatient colposcopy clinic. hrHPV testing revealed a sensitivity of 97% and a specificity of 33% for CIN31. Additional CADM1-M18/MAL-M1 methylation analysis on the hrHPV-positive women increased the specificity to 78% with a sensitivity of 70%. In conclusion, the methylation marker panel CADM1-M18 and MAL-M1 may serve as an alternative molecular triage tool for hrHPV-positive women.Testing for high-risk human papillomavirus (hrHPV) provides a superior protection against cervical (pre-)cancerous lesions compared to cytology and is therefore an attractive primary cervical cancer screening tool. 1-3 However, hrHPV testing is accompanied with a lower specificity for highgrade cervical lesions, due to detection of transient, clinically irrelevant hrHPV infections. The consequence of the latter would be too many undesired adverse effects in the generally healthy population, such as anxiety and overtreatment, leading to pregnancy-associated morbidity. Furthermore, unnecessary high costs of the screening program would be the result. Therefore, triage testing is necessary to distinguish hrHPV-positive women with high-grade cervical intraepithelial neoplasia (CIN) lesions or cervical cancer in need of colposcopy from those without meaningful cervical disease. Currently, cytology is considered an appropriate triage tool when applied as reflex test to hrHPV-positive women. 4 However, cytology is a subjective method that can display highly variable outcomes. Particularly, in case of pre-existing knowledge of hrHPV presence by the cytologist, minor cellular abnormalities might be overcalled, leading to a decl...

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high‐grade cervical intraepithelial neoplasia and cervical cancer (≥CIN3) in high‐risk HPV (hrHPV)‐positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥CIN3 detection in hrHPV‐positive women participating in a prospective observational multi‐center cohort study. The study population comprised hrHPV‐positive women aged 18–66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy‐directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation‐specific PCR (qMSP). Sensitivities and specificities for ≥CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV‐positive women, the sensitivities for ≥CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥30 years (n = 287), ≥CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2–96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0–94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8–68.4) compared to 47.6% (95%CI: 41.1–54.1)]. In conclusion, among hrHPV‐positive women from an outpatient population aged ≥30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥CIN3.

Objective To evaluate the effectiveness of an eHealth intervention on recovery and return to work, after gynaecological surgery.Design Randomised multicentre trial that ran from March 2010 until September 2011.Setting Secondary care in seven general and university hospitals in the Netherlands.Population A cohort of 215 women (aged 18-65 years) who had a hysterectomy and/or laparoscopic adnexal surgery for a benign indication.Methods The women were randomly assigned to the intervention group (n = 110) or the control group (n = 105). The intervention group received an eHealth programme that provided personalised tailor-made pre-and postoperative instructions on the resumption of daily activities, including work, and tools to improve self-empowerment and to identify recovery problems. The control group was provided with access to a control website.Main outcome measures The primary outcome was the duration of sick leave until a full sustainable return to work. Secondary outcome measures were quality of life, general recovery, and pain intensity.Results In intention-to-treat analysis the eHealth intervention was effective on time to return to work (hazard ratio 1.43; 95% confidence interval 1.003-2.040; P = 0.048). The median duration of sick leave until a full sustainable return to work was 39 days (interquartile range 20-67 days) in the intervention group and 48 days (interquartile range 21-69 days) in the control group. After 26 weeks pain intensity was lower (visual analogue scale, cumulative odds ratio 1.84; 95% confidence interval 1.04-3.25; P = 0.035) and quality of life was higher (Rand-36 health survey, between-group difference 30, 95% confidence interval 4-57; P = 0.024) in the intervention group, compared with the control group.Conclusions The use of the eHealth intervention by women after gynaecological surgery results in a faster return to work, with a higher quality of life and less pain.

Objective-The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin. Methods and Results-In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (nϭ49), transdermal 17␤-estradiol (E 2 ) 50 g (tE 2 group, nϭ33), oral E 2 1 mg (oE 2 group, nϭ37), or oral E 2 1 mg combined with gestodene 25 g (oE 2 ϩG group, nϭ33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE 2 , ϩ26.9%; oE 2 , ϩ102.7%; oE 2 ϩG, ϩ69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE 2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE 2 , Ϫ4.1%; oE 2 , Ϫ7.9%; oE 2 ϩG, Ϫ5.8%), free protein S (tE 2 , Ϫ7.1%; oE 2 , Ϫ8.4%; oE 2 ϩG, Ϫ5.2%), and protein C in the oE 2 ϩG group (Ϫ6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr. Conclusions-Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy. Key Words: resistance to activated protein C Ⅲ protein S Ⅲ protein C Ⅲ estrogen replacement therapy Ⅲ venous thrombosis W omen using oral estrogen containing hormone replacement therapy 1-3 or oral contraceptives 4 have an increased risk of developing venous thrombosis. The risk for oral contraceptive users is higher in women who use ethynylestradiol in combination with so-called third-generation progestogens (desogestrel or gestodene) than among women using ethynylestradiol in combination with the secondgeneration progestogen levonorgestrel. 4 This difference might be explained by a differential effect of the progestogens on resistance to activated protein C (APC), 5,6 a risk factor for venous thrombosis. 7,8 It is plausible that the observed increased risk of venous thrombosis in hormone replacement users can also, at least in part, be explained by an increase in resistance to APC.The effect of hormone replacement therapy on resistance to APC, on protein S, and on protein C has been investigated in several studies. However, only few had a randomized, placebo-controlled design. 9 -16 Only uncontrolled 17,18 and cross-sectional 19 studies on the effect of transdermal estradiol on resistance...

Background:High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (⩾CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking.Methods:We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for ⩾CIN3 detection in hrHPV-positive women (n=450,18–66 years).Results:Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with ⩾CIN3 (Spearman's ρ 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women ⩾30 years, ⩾CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75–1.05). In women <30 years, ⩾CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55–1.21). In both groups, ⩾CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes.Conclusions:FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for ⩾CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.