Evaluation of CIN2/3 Lesion Regression in GynTect® DNA Methylation-Marker-Negative Patients in a Longitudinal Study.

Cervical intraepithelial neoplasia (CIN) grade 2/3 has a high spontaneous regression rate, especially among women ≤29 years of age. To reduce overtreatment, reliable prognostic biomarkers would be helpful. The main aim of this study was to analyze the negative predictive value of the methylation marker panel GynTect® for lesion regression. In this prospective, multicenter, longitudinal observational proof-of-concept study, women aged ≤29 years with histologically confirmed CIN2 (n = 24) or CIN3 (n = 36) were closely monitored without treatment for up to 24 or 12 months, respectively. The outcome was either regression, persistence, or progression of the lesion. For each patient, a single baseline sample (V0) for cytology, hrHPV detection and methylation analysis was taken. In a primary analysis, the negative predictive value (NPV) of a GynTect®-negative test result at V0 for regression was determined. We tested the null hypothesis NPV ≤ 70% against the alternative hypothesis NPV ≥ 90%. Twelve of the eighteen GynTect®-negative CIN2 patients showed regression (NPV = 67%, 90% CI 44-85%, p = 0.53). Of the 27 GynTect®-negative CIN3 lesions, 15 regressed (NPV = 56%, 90% CI 38-72%, p = 0.92). Although the majority of GynTect®-negative lesions regressed, the postulated NPV of ≥90% was not observed. Thus, the clinical relevance for an implementation of the GynTect® assay for patients undergoing watchful waiting remains questionable. Further studies with longer observation periods should be undertaken.

Association of two genomic variants with HPV type-specific risk of cervical cancer.

PROBLEM: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. METHODS: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. RESULTS: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03-1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18-7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. CONCLUSIONS: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.

A Therapeutic Antigen-Presenting Cell-Targeting DNA Vaccine VB10.16 in HPV16-Positive High-Grade Cervical Intraepithelial Neoplasia: Results from a Phase I/IIa Trial.

PURPOSE: To evaluate the safety, immunogenicity and efficacy of a therapeutic DNA vaccine VB10.16, using a unique modular vaccine technology that is based on linking antigens to CCL3L1 targeting module, in women with HPV16-positive high-grade cervical intraepithelial neoplasia (CIN). PATIENTS AND METHODS: We conducted a first-in-human, open-label, phase I/IIa clinical trial of VB10.16 in subjects with confirmed HPV16-positive CIN 2/3. The primary endpoint was the proportion of participants with adverse events, including dose-limiting toxicities. Secondary outcome measures included measuring the E6/E7-specific cellular immune response. In the Expansion cohort HPV16 clearance, regression of CIN lesion size and grading were assessed during a 12-month follow-up period. RESULTS: A total of 34 women were enrolled: 16 in two dose cohorts and 18 in the expansion cohort. No serious adverse events or dose-limiting toxicities were observed, and none of the subjects discontinued treatment with VB10.16 due to an adverse event. Mild to moderate injection site reactions were the most commonly reported adverse event (79%). HPV16-specific T-cell responses were observed after vaccination in the majority of the subjects. In the expansion cohort, HPV16 clearance was seen in 8 of 17 evaluable subjects (47%). Reductions in lesion size were seen in 16 subjects (94%) and 10 subjects (59%) had regression to CIN 0/1. Correlation between strong IFNγ T-cell responses and lesion size reduction was statistically significant (P < 0.001). CONCLUSIONS: The novel therapeutic DNA vaccine VB10.16 was well tolerated and showed promising evidence of efficacy and strong HPV16-specific T-cell responses in subjects with high-grade CIN.

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.

Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

Abdominal and Laparoscopic Cervical Carcinoma Therapy - a Comparative Economic Assessment.

Objective The LACC (Laparoscopic Approach to Cervical Cancer) study revealed advantages in terms of overall survival and relapse risk favouring abdominal radical hysterectomy over the laparoscopic procedure. The present paper will compare the two surgical techniques from the economic point of view based on a process cost calculation. Material/Methods A retrospective cost analysis of all radical hysterectomies from the year 2018 was done at the Hanover University Medical School based on the bottoms-up method and guided by the clinical treatment pathway. Result Of 51 primary cases treated, 19 patients underwent radical hysterectomies, of which 8 were performed using the abdominal technique and 11 as endoscopic surgeries. 89.4% of the cancers were FIGO IB1 carcinomas. The total cost of a laparoscopic radical hysterectomy with an average hospital stay of 4.6 days came to € 2512.34, compared to an abdominal radical hysterectomy at € 2586.78 with an average hospital stay of 7.6 days. The greatest cost factor in which the laparoscopic method exceeded abdominal radical hysterectomy was the surgical procedure itself (€ 1836.75 vs. € 1411.21). Personnel represented the largest cost item in the surgical theatre (59%), so that surgery time was a significant multiplying factor. Average surgical time required for abdominal radical hysterectomy was 154 minutes, whereby the laparoscopic procedure required an average of 220.1 minutes. Inpatient care in the abdominal radical procedure cases was more costly by € 499.98 due to the longer hospitalization and additional medication required. Profit levels, including the DRG revenues, were higher with the abdominal method than with the laparoscopic method by € 186.21 despite longer hospital stays. Conclusion The present paper shows slightly greater profitability for the abdominal radical hysterectomy. On the other hand, this method entails longer hospitalization and a higher level of personnel deployment. Adequate occupancy management could make up for the revenue shortfall observed with the laparoscopic method.

CoCoss-Trial: Concurrent Comparison of Self-Sampling Devices for HPV-Detection.

High-risk human papillomavirus (hr-HPV) infection of the cervicovaginal tract is known to be the major cause of cervical cancer. Similar to various other countries, Germany introduced an organized combined screening including cytology and HPV testing in 2020. The participation rate was around 70% in the past. Self-testing for hr-HPV infections could be an option to increase the participation rate. Two dry vaginal self-sampling devices and a device for the self-collection of first-void urine were evaluated in combination with a PCR-based hr-HPV test regarding their clinical performance (sensitivity for high-grade cervical intraepithelial neoplasia, CIN 2+). A cervical smear taken by a clinician during colposcopy was used as reference. This open prospective multicenter trial recruited patients referred to the two participating colposcopy clinics (Hannover Medical School and IZD Hannover, Germany) with abnormal results from cervical cancer screening from 05/2020 to 11/2020. All patients received three CE-certified self-sampling devices (FLOQSwabs, COPAN, Italy; Evalyn Brush, Rovers Medical Devices, the Netherlands; Colli-Pee FV-5000, Novosanis, Wijnegem, Belgium) with instructions to read and apply at home in a pre-specified alternating order without medical assistance. HPV testing was performed after adequate preservation and DNA extraction. Histological results from colposcopy or cervical excisional surgery after self-sampling were used as the gold-standard. The data of 65 patients were analyzed. All invasive cancer cases and over 90% of the CIN 3 lesions were found to be hr-HPV positive with all three self-collection devices. All devices were considered easy to use without any difficulties following the written instructions. Hr-HPV testing of self-collected first-void urine and dry vaginal self-samples showed a high sensitivity for CIN 3+ comparable to that of a clinician-taken smear. Self-sampling was well accepted as it is convenient and easy to use.

[Vaccination against human papillomavirus]. / Impfung gegen humane Papillomviren.

Vaccination against human papillomavirus (HPV), which has been proven to be highly effective and safe, is recommended as part of standard vaccination by the German Standing Committee on Vaccination (STIKO) for 9­ to 14-year-old girls and boys. Up to 90% of cervical cancer and its precancerous lesions can be prevented with timely vaccination (before first intercourse). In addition, the effectiveness extends to the primary prevention of HPV-associated neoplasms of the vulva, vagina, anus, penis and oropharynx. The HPV vaccination is the focus of the global initiative of the WHO calling on German health policymakers to significantly increase the immunization coverage of the German population, which is currently only 45-60%. Due to the high immunogenicity and the convincing long-term effects, the goals of eliminating cervical cancer and significantly reducing other HPV-associated cancers are theoretically achievable.

Performance of a six-methylation-marker assay on self-collected cervical samples - A feasibility study.

OBJECTIVES: In high-income countries, a high proportion of cervical cancers is diagnosed in screening non-attendees. One approach to improve screening coverage is to offer self-sampling for human papillomavirus (HPV) testing. However, especially young women are often HPV positive without having a precancerous lesion in need of treatment. To improve the rather low specificity of HPV testing additional markers such as DNA-methylation can be used. The aim of this feasibility study was to examine the performance of the methylation marker assay GynTect®, comprising six methylation markers, on dry self-collected cervico-vaginal samples compared to physician-taken samples. METHODS: We recruited 89 patients from our colposcopy clinic of whom 87 qualified for the study. The women took a self-sample with the Evalyn-Brush. Afterwards the planned colposcopy was performed and smears for cytology and reference HPV testing were taken as well as a biopsy in cases of abnormalities. Physician-taken and self-collected samples were tested for HPV DNA and were analyzed with GynTect®. RESULTS: We obtained 95.5 % valid results for the self-collected samples which was very close to the physician-taken samples. Only about half of the self-collected samples were GynTect® positive in comparison to the physician-taken samples. GynTect® scores were significantly lower for self-collected than for physician-taken samples (p = 0.001, paired t-test). The overall concordance for GynTect® results was moderate (kappa 0.394; p < 0.001). For HPV testing we obtained a good concordance (kappa 0.586; p < 0.001). The GynTect® results for the self-collected samples showed a sensitivity for the detection of cervical intraepithelial neoplasia 2 or worse (CIN2+) of 26.1 % (95 %-CI: 0.13-0.46) and a specificity of 95.6 % (95 %-CI: 0.85-0.99), in comparison to a sensitivity of 45.5 % (95 %-CI: 0.27-0.65) and a specificity of 78.3 % (95 %-CI: 0.64-0.88) for the physician-taken samples. CONCLUSIONS: GynTect® methylation marker testing has a satisfactory amount of valid results on self-collected samples. However, the results of the self-collected samples differed clearly in comparison to the reference samples. To justify an application in screening, a larger study with more cases of high-grade cervical dysplasia and HPV positive patients will be needed.

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk.

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta-analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case-control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.52, 95% CI 1.14-2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68-0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03-2.36, P = .036) and with high-grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70-0.90, P = 1.9 × 10-4 ; rs2856437: OR 1.58, 95% CI 1.15-2.17, P = .005). A combined analysis of high-grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.57, 95% CI 1.18-2.10, P = .002). No association was detected for rs2856437 with low-grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV-positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8-AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non-HLA cervical cancer susceptibility locus.

Current Approach for External Cephalic Version in Germany.

Introduction Fetal breech presentation at terms occurs in 3 - 6% of pregnancies. External cephalic version can reduce the number of cesarean sections and vaginal breech deliveries. Different approaches are used to carry out external cephalic version. This study looked at the different approaches used in Germany and compared the approach used with the recommendations given in German and international guidelines. Material and Methods An anonymized online survey of 234 hospitals in Germany was carried out in 2018. In addition to asking about hospital structures, questions also focused on how external version was carried out in practice (preparations, tocolysis, anesthetics, etc.), on relative and absolute contraindications and on the success rate. Results 37.2% of the hospitals approached for the survey participated in the study. Of these, 98.8% performed external version procedures. The majority of participating hospitals were university hospitals (26.4%) and maximum care hospitals (35.6%) with an average number of more than 2000 births per year (60.9%). External cephalic version is the preferred (61.7%) obstetrical procedure to deal with breech presentation, rather than vaginal breech birth or primary cesarean section. 45.8% of respondents carry out external version procedures on an outpatient basis, and 42.1% of hospitals perform the procedure as an inpatient intervention, especially from the 37th week of gestation. Prior to performing an external version procedure, 21.6% of surveyed institutions carry out a vaginal examination to evaluate possible fixation of the fetal rump. 95.5% of institutions used fenoterol for tocolytic therapy; the majority using it for continuous tocolysis (70.2%). 1 - 3 attempts at external version (8.4%) were usually carried out by a specific senior physician. In most cases, no analgesics were administered. The reported rate of emergency cesarean sections was very low. The most common indication for emergency C-section was pathological CTG (56,7%). The assessment of relative and absolute contraindications varied, depending on the surveyed hospital. 67.5% asked patients to empty their bladders before carrying out external version, while 10.8% carried out external version when the bladder was filled. The reported success rate was more than 45%. After successful version, only 14.8% of hospitals arranged for patients to wear an abdominal binder. For 32.4%, the decision to apply an abdominal binder was taken on a case-by-case basis. Conclusion The approach used in Germany to carry out external cephalic version is based on the (expired) German guideline on breech presentation. Based on the evidence obtained, a number of individual recommendations should be re-evaluated. More recent international guidelines could be useful to update the standard procedure.

Reproductive capacity and recurrence of disease after surgery for moderate and severe endometriosis - a retrospective single center analysis.

BACKGROUND: Endometriosis can be associated with considerable pain and sterility. After surgical excision of moderate or severe endometriosis lesions, the rate of recurrence reaches up to 67%. The objective of this retrospective study was to establish the recurrence and pregnancy rates following surgical resection of stage III/IV endometriosis lesions. Indications for operation were endometriosis symptoms, sonographic findings and/or infertility. METHODS: A total of 456 patients who underwent stage III/IV endometriosis surgery between 2004 and 2014 were sent a questionnaire relating to their postoperative medical treatment, pregnancies, relief of symptoms and recurrence. Responses of 206 patients (45.2%) and their clinical data were analysed for this study. RESULTS: A total of 66.5% (N = 137) of patients had stage III disease, and 33.5% (N = 69) had stage IV disease. The average age was 37 years (17-59). A total of 63.1% (N = 130) of surgeries were performed by laparoscopy, 21.8% (N = 45) were performed by laparotomy and 15% (N = 31) were performed by conversion. Complete resection of endometriosis lesions was achieved in 90.8% of patients (N = 187). After surgery, 48.5% (N = 100) of the women did not receive hormonal treatment; the main reason was the desire for children in 53%. Complete or partial relief in complaints was achieved in 93.2% (N = 192). The rate of recurrence was 21.8% (N = 45). The statistically significant factors that was associated with a higher risk to develop recurrence was an age < 35 (p < 0.005). After surgery, 65.8% (79/120) of patients who wished to have children became pregnant. There was a statistically significant association among a higher postoperative pregnancy rate and age < 35 (p < 0.003) in multivariate logistic regression analysis and laparoscopic surgical access in univariate logistic regression analysis (p < 0.01). CONCLUSION: We assessed the high percentage of complete or partial relief of symptoms of 93.2%, the high postoperative pregnancy rate of 65.8% and the low rate of recurrence of 21.8% compared to international literature to be very encouraging for women suffering from moderate and severe endometriosis. Though laparoscopy is considered the 'gold standard'of endometriosis surgery, laparotomy still may be indicated in patients with extensive endometriosis especially to preserve reproductive function.

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels.

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10-6 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10-5 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

Peritoneal contamination with ICG-stained cervical secretion as surrogate for potential cervical cancer tumor cell dissemination: A proof-of-principle study for laparoscopic hysterectomy.

INTRODUCTION: Intracorporal colpotomy during radical hysterectomy for cervical cancer is discussed to be a risk factor for peritoneal dissemination of tumor cells. It might lead to increased recurrence rates after laparoscopic radical hysterectomy compared with abdominal hysterectomy, as shown by the recent LACC study. Data on the frequency or mechanisms of peritoneal contamination are missing. We aimed to analyze peritoneal contamination of cervical secretion during intracorporal colpotomy with a novel indocyaningreen (ICG)-based technique. MATERIAL AND METHODS: In this prospective proof-of-principle study, patients undergoing routine laparoscopic or robot-assisted hysterectomy were selected. ICG was specifically applied to the cervical surface and routine surgery was performed. During colpotomy, pictures under white and fluorescence light were taken to evaluate frequency of contamination. RESULTS: By using cervically applied ICG we were able to visualize directly peritoneal contamination with cervical secretion during intracorporal colpotomy. We detected peritoneal contamination in 9/12 (75%) patients undergoing routine laparoscopic hysterectomy. Contamination of laparoscopic instruments occurred in 60% of the patients. When contamination occurred, it was routinely detectable during all steps of colpotomy. There were no adverse effects during surgery. CONCLUSIONS: Peritoneal contamination with cervical secretion frequently occurs during intracorporal colpotomy. This novel technique represents a promising tool for feasible and direct visualization of peritoneal contamination during colpotomy. The technique may be easily implemented in further studies on laparoscopic and abdominal hysterectomy and serve as a quality assessment tool for surgeons and surgical techniques.

Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 1 with Introduction, Screening and the Pathology of Cervical Dysplasia.

Aims Annual opportunistic screening for cervical carcinoma has been carried out in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as the guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. Recommendations The first part of this short summary presents the pathological basis and considers various questions related to screening for cervical cancer. As also reported in earlier reviews, the meta-analysis by Kleijnen Systematic Reviews showed that HPV-based screening offers better protection against invasive cervical cancer compared to cytology-based screening. The authors of this guideline therefore recommend - in accordance with the guideline of the Joint National Committee of Germany (Gemeinsamer Bundesauschuss, G-BA) - that women aged 35 and above should be examined at regular intervals (at least every 3 years) and undergo HPV-based screening. Co-testing can also be carried out. Women between the ages of 20 and 35 should have cytological screening every 2 years.

Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 2 on Triage, Treatment and Follow-up.

Aims Annual opportunistic screening for cervical carcinoma has been done in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as this guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. Recommendations The second part of this short summary deals with the triage, treatment and follow-up care of cervical dysplasia. With regard to those women who do not participate in screening, the guideline authors recommend sending out repeat invitation letters or an HPV self-collection kit. Colposcopy should be carried out for further investigation if cytology findings are Pap II-p and HPV test results are positive or if the results of an HPV 16 or HPV 18 screening test are positive. A single abnormal Pap smear should be triaged and investigated using HPV testing or p16/Ki67 dual staining.

The Value of Partial HPV Genotyping After Conization of Cervical Dysplasias.

INTRODUCTION: In this retrospective study partial genotyping of human papilloma viruses (HPV) using the Abbott RealTime HighRisk HPV Test (RealTime) was compared with simple HPV detection (Qiagen Hybrid Capture 2 Test; hc2) for recurrence prediction at the first follow-up examination after conization of cervical intraepithelial neoplasia (CIN). METHODS: 144 women who had undergone conization for CIN between January 2007 and December 2013 were included. HPV status was determined preoperatively and at first follow-up using hc2 in 103 women and RealTime in 41 women. Recurrent or persistent CIN was assumed when CIN2+ was confirmed histologically or on comparable cytology findings. RESULTS: Of the 144 women with complete data 12 (8.3%) had a recurrence after conization. HPV persistence at follow-up correlated significantly with recurrence (hc2: p = 0.003; RealTime: p = 0.003) and both sensitivity and specificity were high (hc2 = 100 and 78.4% respectively; RealTime = 75.0 and 83.9%). Whereas isolated HPV testing had a relatively low positive predictive value for recurrence (hc2 16%; RealTime 54.5%), this rose to 80% with HPV 16 detection at follow-up. CONCLUSION: At follow-up after conization of CIN the combination of high risk HPV detection and partial genotyping of HPV 16 constitutes excellent diagnostic criteria for recurrence/persistence of CIN.

Application of sentinel lymph node dissection in gynecological cancers: results of a survey among German hospitals.

PURPOSE: Evaluating the application of the sentinel lymph node dissection (SLND) in gynecological cancers among German hospitals. METHODS: Between March and June 2016 an online questionnaire on SLND in gynecologic cancers was sent by email to all German gynecologic cancer centers, all university hospitals and general hospitals for which an email address was available. The survey contained 61 questions regarding the SLND in vulvar, cervical, endometrial and ovarian cancer. RESULTS: In total, 63 clinics, including 13 (20.6%) university hospitals, 28 (44.4%) hospitals offering maximum care and 22 (34.9%) general hospitals, responded to the questionnaire. Most clinics (46/63, 73%) performed SLND in vulvar cancer with a median amount of 7.8 (range 1-43) SLND per year. 56.5% of the clinics included patients according to the German national guidelines and performed ultrastaging of negative SLN. Furthermore, 18/63 (28.5%) of the responding clinics applied SLND in cervical cancer including 7 (77.8%) centers which conducted isolated SLND without radical pelvic lymph node dissection (LND). Preoperative imaging with planar lymphoscintigraphy (LSG) was applied in 12/18 (66.7%) of the clinics. SLND in endometrial cancer was reported by 4/63 (6.4%) hospitals. Three of them (75%) regularly performed a subsequent radical pelvic LND. One clinic (1.5%) reported SLND in ovarian cancer in combination with radical LND. CONCLUSION: Especially in vulvar and cervical cancer, isolated SLND appears to be partially implemented in the routine surgical treatment. However, this survey illustrates a wide heterogeneity regarding inclusion criteria and application of the SLND approach.

Epidemiology and Early Detection of Cervical Cancer.

The new German S3 guideline 'Prevention of Cervical Cancer' published in 2016 is based on the latest available evidence about cervical cancer screening and treatment of cervical precancer. Large randomized controlled trials indicate that human papillomavirus (HPV)-based screening may provide better protection against cervical cancer than cytology alone through improved detection of premalignant disease in the first screening round prior to progression. Therefore, women aged 30 years and older should preferably be screened with HPV testing every 3-5 years (cytology alone every 2 years is an acceptable alternative). Co-testing is not recommended. Screening should start at 25 years using cytology alone every 2 years. The preferred triage test after a positive HPV screening test is cytology. Women positive for HPV 16 and HPV 18 should receive immediate colposcopy. Another alternative triage method is p16/Ki-67 dual stain cytology. The mean yearly participation rate in Germany is between 45 and 50%. Offering devices for HPV self-sampling has the potential to increase participation rates in those women who are at higher risk of developing cervical cancer. Regarding primary prevention, the 9-valent vaccine may provide protection against up to 85% of cervical intraepithelial neoplasia (CIN) 3 and 90% of cervical cancer, and is available in Europe as a 2-dose schedule from May 2016.

Excellent analytical and clinical performance of a dry self-sampling device for human papillomavirus detection in an urban Chinese referral population.

AIM: To evaluate the analytical and clinical effectiveness of cervicovaginal self-sampling with a dry sampling device (Evalyn Brush) for high-risk human papillomavirus (hr-HPV) testing and detection of cervical disease. METHODS: The study population consisted of 101 patients from a large gynecological outpatient clinic in Shanghai referred for abnormal cervical screening results and 101 women without cervical lesions. Self-samples obtained in the clinic and physician-collected cervical specimens (reference) were stored at -20 °C for 16-18 weeks and then transferred to 20 ml of ThinPrep medium and tested for hr-HPV using a multiplex real time polymerase chain reaction assay. All women had a colposcopic examination with a Pap smear and directed or random biopsies. RESULTS: High risk-HPV was detected in 92 patients (45.5%) with the self-collected cervicovaginal specimens and in 93 (46.0%) with the physician-collected cervical specimens, resulting in an agreement of 97.5% and a Kappa of 0.95 (95% confidence interval 0.91-0.99). Among all of the included women, 46 (22.8%) had cervical intraepithelial neoplasia grade 3 or worse (cervical intraepithelial neoplasia 3+). Hr-HPV was found in 43 of these patients (93.5%) with self-sampling and in 44 (95.7%) with the physician-collected specimens. CONCLUSIONS: Self-collected dry cervicovaginal samples transferred to ThinPrep medium and tested for hr-HPV using a clinically validated polymerase chain reaction assay showed very good agreement with physician-collected cervical specimens and a very high hr-HPV positivity rate for cervical intraepithelial neoplasia 3 +.