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In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. This study aimed to describe human papillomavirus HPV type–specific persistence/progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2. We conducted a historical cohort study of women aged 23 to 40 years diagnosed with cervical intraepithelial neoplasia grade 2 at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within 2 years after index diagnosis and no loop electrosurgical excision procedure before this. Human papillomavirus genotyping was performed on archived tissue samples using the HPV SPF 10 -DEIA-LiPA 25 system (DNA ELISA [enzyme-linked immunosorbent assay] HPV SPF10 kit and RHA HPV SPF10-LiPA25 kit). Persistence/progression was defined as having a record of cervical intraepithelial neoplasia grade ≥2 in the DPDB determined on the last and worst diagnosis on a biopsy or loop electrosurgical excision procedure specimen during follow-up. We estimated the relative risk (95% confidence interval) of persistence/progression using a modified Poisson model. A total of 455 women were included. Two-thirds were aged ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had cervical intraepithelial neoplasia grade ≥2 during follow-up; 70.5% were human papillomavirus-16-positive and 29.5% were positive for other human papillomavirus types. Human papillomavirus-16 was associated with a significantly higher risk of persistence/progression (relative risk, 1.64; 95% confidence interval, 1.37–1.95) compared with non-human papillomavirus-16. The risk of persistence/progression was highest in human papillomavirus-16-positive women with a high-grade index cytology compared with human papillomavirus-16-positive women with a low-grade cytology (relative risk, 1.29; 95% confidence interval, 1.03–1.61), whereas no differences were observed across age groups. The highest risk of persistence/progression was observed among human papillomavirus-16-positive women, particularly those with associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women. [ABSTRACT FROM AUTHOR] more...

Abstract: Objective: It has been reported that approximately 10% of low grade squamous intraepithelial lesions (LSIL) progress to high grade squamous intraepithelial lesions (HSIL) within a 2-year follow up. The factors related to lesion progression are currently unknown. The aim of the study was to identify prognostic markers of the course of LSIL. This retrospective study was designed to correlate regression, persistence and progression of biopsy-proven LSIL with patients’ age, HPV genotypes and immunohistochemical expression of the main cell cycle regulating proteins: p53, pRb, p16, and Ki-67. Study design: A total of 584 consecutive patients with biopsy proven LSIL and 2-year follow-up were included in the age analysis. HPV genotyping was performed in 328 LSIL cases using the SPF10 PCR-LiPA25 (version 1), 238 LSIL cases were immunostained for Ki-67 and p16, and 101 cases were immunostained for pRb and p53. Results: The odds of LSIL persistence and progression were significantly higher in women 30–39, 40–49 and 50+ years old, as compared to women 20–29 years old (OR 1.89, 2.52 and 2.39, respectively). The odds of persistence and progression were higher in women infected with HPV16, 18, 33 and 52 (OR 3.5, 3.1, 3.5 and 2.9, respectively). There were no significant differences in expression of immunomarkers (p16, p53, pRB and Ki-67) between the lesions that regressed versus the lesions that persisted or progressed. Conclusions: Patients 30 years of age and older have a higher risk of LSIL progression or persistence as compared to 20–29 year olds. In addition, HPV genotyping, but not the cell cycle markers, may aid in prognosis of LSIL course. [Copyright &y& Elsevier] more...

Objective: To test the hypothesis that abnormal placentation resulting in intrauterine fetal death (IUFD) is associated with coagulation abnormalities in the fetus. Study design: We analyzed fetal DNA from umbilical cords from 139 pregnancies complicated by intrauterine fetal death during 1994–1998 (cases). Fetal DNA was tested for the presence of factor V Leiden and prothrombin G20210A mutations. The prevalence of these thrombophilic mutations among cases were compared with the prevalence in a historic control group. Results: Overall, a higher prevalence of fetal genetic risk factors was found in cases (9.8%) as compared to fetuses born from an uncomplicated pregnancy (2%, odds ratio 4.8, 95% CI 1.1–22). Second trimester intrauterine fetal death occurred more frequently in cases with the factor V Leiden mutation as compared with the control group (8/64 versus 0/92). For intrauterine fetal death and factor V Leiden a high risk was found concerning abruption placentae (odds ratio 7.6, 95% CI 1.5–37). Conclusion: The prevalence of fetal genetic risk factors associated with an increased risk for thrombosis was higher in pregnancies complicated by intrauterine fetal death suggesting an important role of abnormal coagulation in placentation. [Copyright &y& Elsevier] more...

The objective of this article was to evaluate the utility of high-risk human papillomavirus (HR-HPV) testing for triage of women referred for colposcopy because of abnormal smears. We considered women with persistent mild or moderate dyskaryosis and women with severe dyskaryosis who were referred for colposcopy. For both patient groups we evaluated three alternative management policies: (1) conventional management based on histological assessment; (2) HR-HPV-triage with direct treatment without prior histologic assessment for HR-HPV-positive women and conventional management for HR-HPV-negative women; and (3) direct treatment without histologic assessment for all referred women. For each policy the average number of medical procedures, doctor visits, and the costs per referred woman were calculated. Based on a literature review, the results were tested and translated to other patient groups. Per woman with persistent mild or moderate dyskaryosis and compared with conventional policy, HR-HPV-triage will avoid 0.51 colposcopically directed biopsies, but adds 0.05 local treatments of the cervix (i.e., loop excision of the transformation zone) and 0.09 outpatient visits, and will cost $134 US dollars extra. HPV triage is less efficient in women with borderline or mildly dyskaryotic cytology. In women with severe dyskaryosis, direct treatment is more efficient as conventional management or HPV triage. The decision to introduce HPV testing or direct treatment in women with persistent mild or moderate dyskaryosis strongly depends on the relative burden attributed to a colposcopically directed biopsy and an outpatient visit compared to loop excision of the transformation zone treatment of the cervix. For women with severe dyskaryosis, direct treatment should be seriously considered. [ABSTRACT FROM AUTHOR] more...

• Based on tree-based classification analysis, bacterial vaginosis can be best predicted by a positive pH and amine odour test. • A negative pH and odour test excluded bacterial vaginosis as diagnosis, reducing the need for laboratory tests in 50% of the patients. • A qPCR (sensitivity 94%; specificity 97%) performed significant better as confirmation test for bacterial vaginosis than the Nugent score (sensitivity of 59%; specificity 97%; P = 0.031). Abnormal vaginal discharge may be caused by bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis and/or aerobic vaginitis. For the development of a diagnostic algorithm, tree-based classification analysis was performed on symptoms, signs and bedside test results of 56 patients, and laboratory tests (culture, Nugent score, qPCRs) were compared. Amplicon sequencing of the 16S rRNA gene was used as reference test for bacterial vaginosis and aerobic vaginitis, culture for vulvovaginal candidiasis and qPCR for trichomoniasis. For bacterial vaginosis, the best diagnostic algorithm was to screen at the bedside with a pH and odour test and if positive, to confirm by qPCR (sensitivity 94%; specificity 97%) rather than Nugent score (sensitivity of 59%; specificity 97%; P = 0.031). The analysis for the other infections was less conclusive due to the low number of patients with these infections. For bacterial vaginosis, the developed algorithm is sensitive, specific, and reduces the need for laboratory tests in 50% of the patients. [ABSTRACT FROM AUTHOR] more...

Summary: A shift to a molecular approach to cervical cancer screening is the most likely solution to the goals of improved screening in both the developed and developing world. The impetus for new screening technologies in the developed world is predominately driven by the need to increase positive predictive value and reduce over-management of low-grade and often transient abnormalities (i.e., increase specificity). Rapid tests, where results can be given to a patient within the same visit, are anticipated to have the greatest impact in low resource settings in low and middle income countries (and in disadvantaged sub-populations in high-income countries) where substantial loss to follow up cripples the effectiveness of cervical cancer screening programs. Clinical validation will be required before these tests are implemented in routine screening programs. [Copyright &y& Elsevier] more...

Abstract: International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority. [Copyright &y& Elsevier] more...