Evaluation of FAM19A4/miR124-2 methylation performance in the management of CIN3 diagnosed pregnant women.

Pregnant women diagnosed with CIN3 have high regression rates after delivery. Biomarkers are needed to only identify pregnant women with progressive CIN requiring treatment to reduce overreferral and overtreatment. In our study we evaluated the performance of the FAM19A4/miR124-2 methylation test for molecular triage on FFPE samples of CIN3+-diagnosed pregnant women with known clinical course over time as well in a cross-sectional setting. In this German multicenter retrospective study biopsy material was collected from pregnant women diagnosed with cervical cancer (n = 16), with CIN3 that progressed to cancer during pregnancy (n = 7), with CIN3 that regressed to CIN1 or less within 6 months after delivery (n = 41), without CIN (n = 16), CIN3 covering 3-4 quadrants (n = 14) and randomly selected CIN3 (n = 41). FAM19A4/miR124-2 methylation analysis was performed blinded on first diagnosis. All pregnant women with cervical cancer and with CIN3 progressing to cancer tested positive for FAM19A4/miR124-2 methylation (100%, 22/22). In the regressing CIN3 group 47.5% and in the group without CIN 21.6% tested methylation positive. High-volume CIN3 and random selected CIN3 were methylation-positive in 91.7% and 82.1%, respectively. Methylation levels were significantly higher in progressive CIN3 and cancer compared to the controls (P < .0005). The likelihood ratio of a negative methylation test (LR-) for progressive CIN3+ was 0 (95% CI: 0-0.208). A negative FAM19A4/miR124-2 methylation test can rule out progressive CIN disease in pregnant women diagnosed with CIN3. This can help the clinician by managing these pregnant women with conservative follow-up until after delivery.

Classification of high-grade cervical intraepithelial neoplasia by p16ink4a , Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management.

High-grade cervical intraepithelial neoplasia (CIN2 and CIN3) represents a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16ink4a , Ki-67 and host-cell DNA methylation) could provide guidance for clinical management in women with high-grade CIN. This study evaluates the cumulative score of immunohistochemical expression of p16ink4a (Scores 0-3) and Ki-67 (Scores 0-3), referred to as the "immunoscore" (IS), in 262 CIN2 and 235 CIN3 lesions derived from five European cohorts in relation to immunohistochemical HPV E4 expression and FAM19A4/miR124-2 methylation in the corresponding cervical scrape. The immunoscore classification resulted in 30 lesions within IS group 0-2 (6.0%), 151 lesions within IS group 3-4 (30.4%) and 316 lesions within IS group 5-6 (63.6%). E4 expression decreased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). Methylation positivity increased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (Ptrend < .001). E4 expression was present in 9.8% of CIN3 (23/235) and in 12.0% of IS group 5-6 (38/316). Notably, in a minority (43/497, 8.7%) of high-grade lesions, characteristics of both transforming HPV infection (DNA hypermethylation) and productive HPV infection (E4 expression) were found simultaneously. Next, we stratified all high-grade CIN lesions, based on the presumed cancer progression risk of the biomarkers used, into biomarker profiles. These biomarker profiles, including immunoscore and methylation status, could help the clinician in the decision for immediate treatment or a "wait and see" policy to reduce overtreatment of high-grade CIN lesions.

Estimation of the incidence of genital warts and the cost of illness in Germany: a cross-sectional study.

BACKGROUND: Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign condylomata acuminata, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease. METHODS: This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated. RESULTS: For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14-65 years consulting gynecologists. The highest incidence was observed in women aged 14-25 years (171.0 per 100 000) for new cases and in women aged 26-45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8-444.9); for recurrent genital warts at 603 euros (95% CI: 436.5-814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6-1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively. CONCLUSION: The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.

Management options for cervical intraepithelial neoplasia.

Management of cervical intraepithelial neoplasia (CIN) needs to protect women at risk from developing cervical cancer and to avoid over-treatment as well as obstetrical complications in women undergoing invasive treatment. Strong evidence shows that CIN3 is a true precursor and must be treated, whereas CIN1 lesions do not benefit from immediate surgery and should be followed conservatively. Although the clinical course of CIN2 differs from CIN3, it should be treated the same way for legal reasons. Colposcopy plays a central role in selection of patients and treatments. Treatment of CIN2 and 3 should be excisional. Large loop excision of the transformation zone, high-frequency-needle or laser conisation are equally good, whereas cold-knife conisation is associated with an excess risk for subsequent obstetrical complications. Human papillomavirus testing and cytology at 6 months seems to be the best post-treatment monitoring, although this needs to be confirmed by randomised-controlled trials. Future research needs to focus more on how the quality of colposcopy and the overall management concept determines the clinical outcome instead of exploring the role of single technical methods. Furthermore, it seems to be necessary to evaluate the best management of CIN2 in young and in vaccinated women.

Adopting Guidelines into Clinical Practice: Implementation of Trastuzumab in the Adjuvant Treatment of Breast Cancer in Lower Saxony, Germany, in 2007.

SUMMARY: BACKGROUND: Few studies have assessed the quality of medical care in breast cancer patients outside clinical studies and certified centres in German-speaking countries. We used ONkeyLINE, a voluntary tumour registry, to evaluate the rate of adoption into clinical practice of guidelines on the adjuvant use of trastuzumab and to estimate the reliability of ONkeyLINE in assessing quality of care. MATERIAL AND METHODS: Data from ONkeyLINE were analysed to answer questions on the quality of breast cancer care in daily practice in 2007. The influence of age and area (rural/urban) on treatment patterns was also evaluated. RESULTS: Data from approximately 85% of patients diagnosed with breast cancer in Lower Saxony in 2007 were documented in ONkeyLINE. Within 1 year, more than 77% of patients received adjuvant trastuzumab according to the updated guidelines. Variations in chemotherapy and trastuzumab according to age were evident, in part but not fully attributable to comorbidities in the elderly. Access to trastuzumab therapy in rural areas was as high as in urban areas. CONCLUSIONS: Adoption of national guidelines into clinical practice was observed at a reasonable but still unsatisfactory rate in Lower Saxony. Although voluntary, ONkeyLINE covered most breast cancer cases and proved to be a reliable tool for assessing quality of care.

Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study.

PURPOSE: This open-label, randomized phase III study was designed to investigate the effects of erythropoietin alfa (EPO) in addition to adjuvant chemotherapy and pelvic radiotherapy (CRT) in patients with stage IB to II cervical cancer who had undergone radical hysterectomy. PATIENTS AND METHODS: Two hundred fifty-seven patients were randomly assigned to four cycles of carboplatin/ifosfamide chemotherapy followed by external-beam pelvic radiotherapy (CRT group) or four cycles of carboplatin/ifosfamide chemotherapy and EPO followed by pelvic radiotherapy and EPO (CRT + EPO group). The primary end point was recurrence-free survival (RFS). Secondary end points included overall survival (OS), change in hemoglobin levels, and safety, including thromboembolic events. RESULTS: The estimated 5-year RFS rates were 78% for patients receiving CRT + EPO and 70% for patients receiving CRT. There was no statistically significant difference in RFS, although a trend favoring patients treated with CRT + EPO was observed (hazard ratio [HR], 0.66; 95% CI, 0.39 to 1.12; log-rank P = .06). Exploratory analyses suggest a benefit with CRT + EPO for patients with stage IB to IIA disease (HR, 0.39; 95% CI, 0.18 to 0.85; P = .014) or patients with complete resection (HR, 0.55; 95% CI, 0.31 to 0.98; P = .039). OS was similar in both groups (HR, 0.88; 95% CI, 0.51 to 1.50; log-rank P = .63). Patients treated with EPO maintained higher hemoglobin levels throughout CRT. No significant differences in safety profiles were observed between the two groups. Incidence of thrombovascular events was low (2%) and comparable between both groups. CONCLUSION: This study confirms that EPO can be added safely to CRT in patients with cervical cancer, but it failed to demonstrate a significant benefit in RFS and OS.